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29 results on '"MESH: Angiotensin II"'

1. Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19

Author

Lucy Kundura, Sandrine Gimenez, Renaud Cezar, Sonia André, Mehwish Younas, Yea-Lih Lin, Pierre Portalès, Claire Lozano, Charlotte Boulle, Jacques Reynes, Thierry Vincent, Clément Mettling, Philippe Pasero, Laurent Muller, Jean-Yves Lefrant, Claire Roger, Pierre-Géraud Claret, Sandra Duvnjak, Paul Loubet, Albert Sotto, Tu-Anh Tran, Jérôme Estaquier, Pierre Corbeau, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Initial MAnagement and prevention of acute orGan failures IN critically ill patiEnts (IMAGINE), Université de Montpellier (UM), Laboratoire de Bioingénierie et NanoSciences (LBN), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Virulence Bactérienne et Infections Chroniques (VBIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), and ANR-21-COVR-0024,ACT-LONG-COVID,Caractérisation clinique et biologique du syndrome d'activation mastocytaire dans le COVID long et prédisposition génétique(2021)

Subjects
T-Lymphocytes, Immunology, ACE2, Apoptosis, MESH: Lymphopenia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Lymphopenia, Humans, MESH: COVID-19, Immunology and Allergy, MESH: SARS-CoV-2, DNA oxidation, Programmed cell death, MESH: DNA Damage, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Humans, SARS-CoV-2, Angiotensin II, COVID-19, MESH: Reactive Oxygen Species, MESH: T-Lymphocytes, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Oxidative stress, Angiotensin II receptor, MESH: Angiotensin II, MESH: Apoptosis COVID-19, Antioxidant, Reactive Oxygen Species, DNA Damage
Abstract

International audience; Background: Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19).Objective: The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Methods: Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n 5 29) or not admitted to an ICU (n 5 29) and in ageand sex-matched healthy controls.Results: We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, angiotensin-converting enzyme 2, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes.Conclusion: We conclude that T-cell apoptosis provoked via DNA damage due to the release of monocytic ROSs could play a major role in COVID-19 pathogenesis.

Published
2022
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2. α1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction

Author

Marc Foretz, Moritz Brandt, Eberhard Schulz, Philip Wenzel, Matthias Oelze, John F. Keaney, Swenja Kröller-Schön, Thomas Münzel, Benoit Viollet, Thomas Jansen, Andreas Daiber, Sebastian Steven, Jeremy Lagrange, Miroslava Kvandova, Sanela Kalinovic, Tanja Schönfelder, Johannes Gutenberg - Universität Mainz (JGU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and Johannes Gutenberg - University of Mainz (JGU)

Subjects
MESH: Signal Transduction, 0301 basic medicine, CCR2, Physiology, medicine.medical_treatment, MESH: Aortic Diseases, AMP-Activated Protein Kinases, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, 0302 clinical medicine, MESH: Animals, MESH: AMP-Activated Protein Kinases, Aorta, Cells, Cultured, Mice, Knockout, MESH: Cytokines, MESH: Oxidative Stress, biology, Chemistry, Angiotensin II, MESH: Genetic Predisposition to Disease, MESH: Aorta, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Respiratory burst, Vasodilation, Phenotype, Cytokine, Cytokines, Tumor necrosis factor alpha, MESH: Angiotensin II, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, Signal Transduction, MESH: Cells, Cultured, MESH: Inflammation Mediators, Aortic Diseases, Inflammation, MESH: Phenotype, MESH: Vasodilation, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, Physiology (medical), medicine, Animals, Genetic Predisposition to Disease, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Interleukin 6, Macrophages, MESH: Macrophages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, MESH: Gene Deletion, Cancer research, biology.protein, MESH: Disease Models, Animal, Gene Deletion
Abstract

Aims Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.

Published
2018
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3. Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated kidney, eye and vessel injury

Author

Pierre-Louis Tharaux, Véronique Baudrie, Christophe Roubeix, Anna Chipont, Léa Guyonnet, Matthew A. Bailey, Tariq E. Farrah, Alicja Czopek, David C. Kluth, David J. Webb, Philippe Bonnin, Olivia Lenoir, Florian Sennlaub, Neeraj Dhaun, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Edinburgh, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, Hal Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.medical_specialty, Myeloid, hypertension, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Inflammation, Blood Pressure, Kidney, MESH: Hypertension, organ injury, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, medicine, Animals, MESH: Animals, Receptor, MESH: Mice, MESH: Endothelins, business.industry, Angiotensin II, Endothelins, Glomerulosclerosis, MESH: Blood Pressure, MESH: Kidney, medicine.disease, Receptor, Endothelin B, MESH: Receptor, Endothelin B, macrophages, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, Blood pressure, medicine.anatomical_structure, Basic Research, Nephrology, MESH: Angiotensin II, medicine.symptom, business, Endothelin receptor, endothelin
Abstract

The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages., Graphical abstract

Published
2020
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4. Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction

Author

Andreas Daiber, Marc Foretz, Matthias Oelze, Sabine Kossmann, Philip Wenzel, Thomas Münzel, Jeremy Lagrange, Katie Frenis, John F. Keaney, Eberhard Schulz, Thi Lan P. Tran, Thomas Jansen, Benoit Viollet, Swenja Kröller-Schön, Miroslawa Kvandová, Sanela Kalinovic, Johannes Gutenberg - Universität Mainz (JGU), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), and Johannes Gutenberg - University of Mainz (JGU)

Subjects
Male, 0301 basic medicine, MESH: Inflammation, Physiology, AMP-Activated Protein Kinases, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Mice, Knockout, Antioxidants, Mice, 0302 clinical medicine, MESH: Animals, Endothelial dysfunction, MESH: AMP-Activated Protein Kinases, Vascular inflammation, Mice, Knockout, NADPH oxidase, MESH: Oxidative Stress, biology, MESH: Heme Oxygenase-1, Chemistry, Angiotensin II, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, α1AMPK, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Integrin alpha M, Knockout mouse, MESH: Angiotensin II, MESH: Membrane Proteins, MESH: Endothelium, Vascular, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, 03 medical and health sciences, Downregulation and upregulation, MESH: Mice, Inbred C57BL, Physiology (medical), Internal medicine, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, Inflammation, Macrophages, MESH: Antioxidants, Membrane Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Mice, Inbred C57BL, Heme oxygenase, Oxidative Stress, 030104 developmental biology, Endocrinology, biology.protein, Endothelium, Vascular, Reactive oxygen species, Heme Oxygenase-1, Oxidative stress
Abstract

International audience; Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6G-Ly6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.

Published
2019
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5. Modulation by bradykinin and nitric oxide of angiotensin II-induced apoptosis in a vascular smooth muscle cell phenotype

Author

Jean-Pierre Girolami, S. Colie, Christiane Pecher, Nelly Blaes, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise

Subjects
Nitroprusside, medicine.medical_specialty, Programmed cell death, Vascular smooth muscle, MESH: Rats, Cell Survival, Immunology, Bradykinin, Apoptosis, Biology, Nitric Oxide, MESH: Phenotype, Muscle, Smooth, Vascular, Nitric oxide, chemistry.chemical_compound, Annexin, Internal medicine, medicine, Animals, Immunology and Allergy, MESH: Animals, Rats, Wistar, Pharmacology, MESH: Bradykinin, Angiotensin II receptor type 1, Angiotensin II, MESH: Apoptosis, MESH: Rats, Wistar, MESH: Muscle, Smooth, Vascular, musculoskeletal system, MESH: Nitroprusside, Rats, Phenotype, Endocrinology, MESH: Cell Survival, chemistry, MESH: Nitric Oxide, cardiovascular system, MESH: Angiotensin II, tissues
Abstract

International audience; There is evidence for a clinical benefit of ACE inhibitors or AT1 antagonists in cardiovascular diseases with deleterious smooth muscle cells (SMC) apoptosis. We have previously shown that angiotensin II (Ang II) induces a phenotype-dependent SMC apoptosis. We asked whether bradykinin (BK) and nitric oxide (NO) could modulate Ang II-induced SMC apoptosis. BK alone did not induce significant apoptosis in either spindle (Sp-SMC) or epithelioid (Ep-SMC) SMC phenotypes cultured in serum reduction, but phenotype-dependently, reduced cell proliferation. Pretreatment with BK partly impaired Ang II-induced reduction of Ep-SMC culture viability and partly prevented apoptotic features. Pretreatment with sodium nitroprusside completely prevented all Ang II-induced deleterious effects in Ep-SMC, i. e. reduction of culture viability, Annexin V binding, nuclear condensation and cell fragmentation. These findings indicate that the BK-NO system may phenotype-dependently modulate SMC survival and in particular may oppose, mostly by NO, Ang II-induction of apoptosis in the Ep-SMC phenotype.

Published
2008
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6. Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Author

François Duhamel, Philippe Coulombe, Sylvain Meloche, Stephane Pelletier, Michel R. Popoff, Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Bactéries anaérobies et Toxines, Institut Pasteur [Paris] (IP), This work was supported by a grant to S.M. from the Canadian Institutes for Health Research (CIHR, MOP-14650). S.P. and P.C. are the recipients of studentships from the Heart and Stroke Foundation of Canada and the CIHR, respectively., and Institut Pasteur [Paris]

Subjects
rac1 GTP-Binding Protein, rho GTP-Binding Proteins, MESH: Signal Transduction, Transcription, Genetic, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, GTPase, Antioxidants, Muscle, Smooth, Vascular, MESH: Janus Kinase 2, Receptor tyrosine kinase, MESH: Tyrosine, MESH: Thrombin, chemistry.chemical_compound, 0302 clinical medicine, MESH: Oxidants, MESH: STAT2 Transcription Factor, MESH: Animals, Phosphorylation, STAT3, Cell Growth and Development, Cells, Cultured, 0303 health sciences, Angiotensin II, Thrombin, MESH: Reactive Oxygen Species, MESH: STAT3 Transcription Factor, MESH: Muscle, Smooth, Vascular, Protein-Tyrosine Kinases, Oxidants, Cell biology, DNA-Binding Proteins, STAT1 Transcription Factor, Biochemistry, 030220 oncology & carcinogenesis, MESH: Angiotensin II, Signal transduction, Signal Transduction, MESH: Cells, Cultured, STAT3 Transcription Factor, MESH: Mutation, MESH: GTP-Binding Proteins, MESH: Rats, MESH: Trans-Activators, Bacterial Toxins, MESH: Receptors, Cytoplasmic and Nuclear, Biology, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, GTP-Binding Proteins, Proto-Oncogene Proteins, Animals, Humans, Molecular Biology, 030304 developmental biology, G protein-coupled receptor, MESH: Humans, MESH: Phosphorylation, MESH: rac1 GTP-Binding Protein, MESH: Transcription, Genetic, MESH: Antioxidants, STAT2 Transcription Factor, Tyrosine phosphorylation, Cell Biology, Janus Kinase 2, MESH: rho GTP-Binding Proteins, Rats, MESH: Proto-Oncogene Proteins, MESH: Bacterial Toxins, chemistry, Mutation, Trans-Activators, biology.protein, Tyrosine, MESH: STAT1 Transcription Factor, Reactive Oxygen Species, Janus kinase, MESH: DNA-Binding Proteins
Abstract

International audience; As do cytokine receptors and receptor tyrosine kinases, G protein-coupled receptors (GPCRs) signal to Janus kinases (Jaks) and signal transducers and activators of transcription (STATs). However, the early biochemical events linking GPCRs to this signaling pathway have been unclear. Here we show that GPCR-stimulated Rac activity and the subsequent generation of reactive oxygen species are necessary for activating tyrosine phosphorylation of Jaks and STAT-dependent transcription. The requirement for Rac activity can be overcome by addition of hydrogen peroxide. Expression of activated mutants of Rac1 is sufficient to activate Jak2 and STAT-dependent transcription, and the activation of Jak2 correlates with the ability of Rac1 to bind to NADPH oxidase subunit p67(phox). We further show that GPCR agonists stimulate tyrosine phosphorylation of STAT1 and STAT3 proteins in a Rac-dependent manner. The tyrosine phosphorylation of STAT3 is biphasic; the first peak of phosphorylation is weak and correlates with rapid activation of Jaks by GPCRs, whereas the second peak is stronger and requires the synthesis of an autocrine factor. Rho also plays an essential role in the induction of STAT transcriptional activity. Our results highlight a novel role for Rho GTPases in mediating the regulatory effects of GPCRs on STAT-dependent gene expression.

Published
2003
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7. Photoreleasable ligands to study intracrine angiotensin II signalling

Author

Artavazd, Tadevosyan, Myriam, Létourneau, Benjamin, Folch, Nicolas, Doucet, Louis R, Villeneuve, Aida M, Mamarbachi, Darlaine, Pétrin, Terence E, Hébert, Alain, Fournier, David, Chatenet, Bruce G, Allen, Stanley, Nattel, Département de Médecine, Faculté de Médecine, Montreal Heart Institute, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Université de Sherbrooke (UdeS)-Université Laval [Québec] (ULaval)-McGill University = Université McGill [Montréal, Canada]-University of Ottawa [Ottawa]-Université du Québec à Trois-Rivières (UQTR)-Université de Montréal (UdeM)-TransBiotech, Lévis-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Groupe de Recherche Axé sur la Structure des Protéines (GRASP), McGill University = Université McGill [Montréal, Canada], Department of Pharmacology and Therapeutics [Montréal], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Montréal (UdeM), and The present study was supported by grants from the Canadian Institutes for Health Research (CIHR, 6957 and 68929), theQuebec Heart and Stroke Foundation, and the Fondation Leducq(ENAFRANetwork,07/CVD/03).A.T.wa ssupported byan FRQS-RSCV/HSFQ doctoral scholarship. B.F. was supported by a postdoctoral fellowship from the ‘Fondation universitaireArmand-Frappier de l’INRS ’and a Banting Research Foundation grant

Subjects
Male, MESH: Rats, Ultraviolet Rays, MESH: Fluoresceins, [SDV]Life Sciences [q-bio], MESH: Receptors, Angiotensin, MESH: Microscopy, Fluorescence, MESH: Rats, Sprague-Dawley, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Calcium Signaling, Rats, Sprague-Dawley, Angiotensin Receptor Antagonists, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Animals, Humans, MESH: Animals, Calcium Signaling, Fluorescent Dyes, Receptors, Angiotensin, MESH: Humans, Angiotensin II, Fluoresceins, MESH: Fluorescent Dyes, MESH: Male, Rats, HEK293 Cells, MESH: Angiotensin Receptor Antagonists, Microscopy, Fluorescence, MESH: HEK293 Cells, cardiovascular system, MESH: Ultraviolet Rays, MESH: Angiotensin II, Techniques for Physiology, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; The renin-angiotensin system plays a key role in cardiovascular physiology and its overactivation has been implicated in the pathogenesis of several major cardiovascular diseases. There is growing evidence that angiotensin II (Ang-II) may function as an intracellular peptide to activate intracellular/nuclear receptors and their downstream signalling effectors independently of cell surface receptors. Current methods used to study intracrine Ang-II signalling are limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we present novel photoreleasable Ang-II analogues used to probe intracellular actions with spatial and temporal precision. The photorelease of intracellular Ang-II causes nuclear and cytosolic calcium mobilization and initiates the de novo synthesis of RNA in cardiac cells, demonstrating the application of the method. Several lines of evidence suggest that intracellular angiotensin II (Ang-II) contributes to the regulation of cardiac contractility, renal salt reabsorption, vascular tone and metabolism; however, work on intracrine Ang-II signalling has been limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we aimed to synthesize and characterize cell-permeant Ang-II analogues that are inactive without uncaging, but release active Ang-II upon exposure to a flash of UV-light, and act as novel tools for use in the study of intracrine Ang-II physiology. We prepared three novel caged Ang-II analogues, [Tyr(DMNB)(4)]Ang-II, Ang-II-ODMNB and [Tyr(DMNB)(4)]Ang-II-ODMNB, based upon the incorporation of the photolabile moiety 4,5-dimethoxy-2-nitrobenzyl (DMNB). Compared to Ang-II, the caged Ang-II analogues showed 2-3 orders of magnitude reduced affinity toward both angiotensin type-1 (AT1R) and type-2 (AT2R) receptors in competition binding assays, and greatly-reduced potency in contraction assays of rat thoracic aorta. After receiving UV-irradiation, all three caged Ang-II analogues released Ang-II and potently induced the contraction of rat thoracic aorta. [Tyr(DMNB)(4)]Ang-II showed the most rapid photolysis upon UV-irradiation and was the focus of subsequent characterization. Whereas Ang-II and photolysed [Tyr(DMNB)(4)]Ang-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R), caged [Tyr(DMNB)(4)]Ang-II did not. Cellular uptake of [Tyr(DMNB)(4)]Ang-II was 4-fold greater than that of Ang-II and significantly greater than uptake driven by the positive-control HIV TAT(48-60) peptide. Intracellular photolysis of [Tyr(DMNB)(4)]Ang-II induced an increase in nucleoplasmic Ca(2+) ([Ca(2+)]n), and initiated 18S rRNA and nuclear factor kappa B mRNA synthesis in adult cardiac cells. We conclude that caged Ang-II analogues represent powerful new tools for use in the selective study of intracrine signalling via Ang-II.

Published
2015
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8. Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase

Author

Irina Lobysheva, Dominique Langin, Jean-Luc Balligand, A.C. Pouleur, Annelies Vanderper, Konrad R. Götz, Karima Jnaoui, Christophe Beauloye, Denise Hilfiker-Kleiner, Andreas Markl, Hrag Esfahani, Emilie Dubois-Deruy, Luc Bertrand, Guido Iaccarino, Joanna Hammond, Geneviève Tavernier, Paul Herijgers, Viacheslav O. Nikolaev, Julien Hamelet, Catharina Belge, Chantal Dessy, Boris Manoury, Belge, C., Hammond, J., Dubois-Deruy, E., Manoury, B., Hamelet, J., Beauloye, C., Markl, A., Pouleur, A. -C., Bertrand, L., Esfahani, H., Jnaoui, K., Gotz, K. R., Nikolaev, V. O., Vanderper, A., Herijgers, P., Lobysheva, I., Iaccarino, G., Hilfiker-Kleiner, D., Tavernier, G., Langin, D., Dessy, C., Balligand, J. -L., Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain = Catholic University of Louvain (UCL), Pole of Cardiovascular Pathology and Cliniques Universitaires Saint-Luc, Division of Cardiology and Pneumology, University of Göttingen - Georg-August-Universität Göttingen, Department of Cardiovascular Sciences, Department of Medicine and Surgery, Università degli Studi di Salerno (UNISA)-RCCS 'Multimedia', Molecular Cardiology, Medizinische Hochschule Hannover (MHH), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Georg-August-University = Georg-August-Universität Göttingen, and Università degli Studi di Salerno = University of Salerno (UNISA)-RCCS 'Multimedia'

Subjects
MESH: Signal Transduction, Male, MESH: Myocytes, Cardiac, MESH: Neurotransmitter Agents, MESH: Isoproterenol, Muscle hypertrophy, Heart Ventricle, chemistry.chemical_compound, Mice, Cyclic GMP-Dependent Protein Kinase, MESH: Cyclic GMP-Dependent Protein Kinases, Myocyte, MESH: Cyclic GMP, MESH: Animals, Myocytes, Cardiac, Cyclic GMP, Cells, Cultured, Neurotransmitter Agents, biology, MESH: Hypertrophy, Ventricular Remodeling, Angiotensin II, Receptors, adrenergic, beta, Nitric oxide synthase, Catecholamine, MESH: Nitric Oxide Synthase, MESH: Angiotensin II, Signal transduction, Cardiology and Cardiovascular Medicine, MESH: Cells, Cultured, Human, Signal Transduction, medicine.medical_specialty, MESH: Mice, Transgenic, Heart Ventricles, MESH: Ventricular Remodeling, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In Vitro Techniques, Nitric oxide, Neurotransmitter Agent, Physiology (medical), Internal medicine, medicine, Cyclic GMP-Dependent Protein Kinases, Animals, Humans, Ventricular remodeling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: Humans, business.industry, Animal, In Vitro Technique, Isoproterenol, Hypertrophy, medicine.disease, MESH: Male, Disease Models, Animal, Endocrinology, chemistry, Receptors, Adrenergic, beta-3, biology.protein, MESH: Heart Ventricles, MESH: Disease Models, Animal, Nitric Oxide Synthase, business, MESH: Receptors, Adrenergic, beta-3, cGMP-dependent protein kinase
Abstract

Background— β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Methods and Results— Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Conclusions— Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

Published
2014
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9. A CD31-derived peptide prevents angiotensin II-induced atherosclerosis progression and aneurysm formation

Author

Jean-Baptiste Michel, Emilie Groyer, Giuseppina Caligiuri, Antonino Nicoletti, Kevin Guedj, Srini V. Kaveri, Jamila Khallou-Laschet, Alain Tedgui, Marc Clement, Giulia Fornasa, Anh Thu Gaston, Marion Morvan, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported in part by the 'Fondation de France' (Engt 2008-002724), the 'Agence Nationale de la Recherche' (project 'RELATE' and project 'BROSCI'), and the 'Fighting Aneurysmal Disease' (FAD, #217, European integrated project 'Health-F2-2008-200647'). G.F. was the recipient of grants from the 'Groupe de Reflexion sur la Recherche Cardio-Vasculaire', 'Fe'deration Franc¸aise de Cardiologie' and 'Fondation pour la Recherche Me'dicale'. M.C. is the recipient of a doctoral grant provided by the 'CODDIM' from the Region Iˆle de France., European Project: 200647,EC:FP7:HEALTH,FP7-HEALTH-2007-A,FAD(2008), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Caligiuri, Giuseppina, and Fighting Aneurysmal Diseases - FAD - - EC:FP7:HEALTH2008-07-01 - 2012-06-30 - 200647 - VALID

Subjects
Male, Apolipoprotein E, Pathology, Time Factors, Physiology, T-Lymphocytes, Anti-Inflammatory Agents, MESH: Aortic Diseases, MESH: Chemotaxis, Leukocyte, Peptide, 030204 cardiovascular system & hematology, Pharmacology, Lymphocyte Activation, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, MESH: Atherosclerosis, Mice, Aortic aneurysm, 0302 clinical medicine, MESH: Animals, Receptor, Cells, Cultured, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, MESH: Peptides, Angiotensin II, MESH: Macrophage Activation, MESH: Receptors, Antigen, T-Cell, MESH: Apolipoproteins E, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Platelet Endothelial Cell Adhesion Molecule-1, Chemotaxis, Leukocyte, cardiovascular system, MESH: Angiotensin II, Cardiology and Cardiovascular Medicine, MESH: Aortic Aneurysm, Abdominal, MESH: Cells, Cultured, medicine.medical_specialty, Aortic Diseases, Receptors, Antigen, T-Cell, Biology, 03 medical and health sciences, Apolipoproteins E, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Physiology (medical), Renin–angiotensin system, Extracellular, medicine, Animals, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, Dose-Response Relationship, Drug, MESH: Time Factors, MESH: Antigens, CD31, Macrophage Activation, medicine.disease, Atherosclerosis, Aneurysm, MESH: Male, Disease Models, Animal, MESH: T-Lymphocytes, chemistry, MESH: Anti-Inflammatory Agents, CD31, MESH: Disease Models, Animal, Peptides, Aortic Aneurysm, Abdominal
Abstract

International audience; AIMS: The loss of the inhibitory receptor CD31 on peripheral T lymphocytes is associated with the incidence of atherosclerotic complications such as abdominal aortic aneurysms (AAA) in patients and plaque thrombosis in mice. However, we have recently discovered that a small fragment of extracellular CD31 remains expressed on the surface of the apparently 'CD31-negative' T-cells and that it is possible to restore the CD31-mediated T-cell inhibition in vivo by using a synthetic CD31-derived peptide. Here, we wanted to evaluate the therapeutic potential of the peptide in an experimental model of accelerated atherosclerosis and AAA formation. METHODS AND RESULTS: The effect of the murine CD31-derived peptide (aa 551-574, 1.5 mg/kg/day, sc) was evaluated on the extent of atherosclerotic plaques and the incidence of AAA in 28-week-old apolipoprotein E knockout mice (male, n ≥ 8/group) submitted to chronic angiotensin II infusion. The therapeutic mechanisms of the peptide were assessed by evaluating its effect on immune cell functions in vivo and in vitro. The prevalence of angiotensin II-induced AAA correlated with the loss of extracellular CD31 on T-cells. CD31 peptide treatment reduced both aneurysm formation and plaque size (P < 0.05 vs. control). Protection was associated with reduced perivascular leucocyte infiltration and T-cell activation in vivo. Functional in vitro studies showed that the peptide is able to suppress both T-cell and macrophage activation. CONCLUSION: CD31 peptides could represent a new class of drugs intended to prevent the inflammatory cell processes, such as those underlying progression of atherosclerosis and development of AAA.

Published
2012
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10. WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice

Author

Sonia Bergaya, Xavier Jeunemaitre, Juliette Hadchouel, Gervaise Loirand, Marc Rio, Jean-Michel Achard, Brigitte Escoubet, Daniel Henrion, Sébastien Faure, Véronique Baudrie, Philippe Bonnin, Département de physiologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Architecture, Ville, Urbanisme, Environnement (LAVUE), École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Ministère de la Culture (MC)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Nanterre (UPN)-Ministère de la Culture (MC)-Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Nanterre (UPN)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Angers, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Architecture, Ville, Urbanisme, Environnement ( LAVUE ), Université Paris 8 Vincennes-Saint-Denis ( UP8 ) -Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), and Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Male, MESH: Phenylephrine, MESH : Carotid Arteries, Blood Pressure, MESH : Blotting, Western, MESH : Mice, 129 Strain, Mice, Phenylephrine, MESH : Phosphorylation, 0302 clinical medicine, MESH: Animals, 0303 health sciences, MESH : Vasoconstrictor Agents, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Blood Pressure, MESH : Norepinephrine, MESH: Vasoconstriction, MESH: Haploinsufficiency, MESH : Vasoconstriction, MESH : Haploinsufficiency, medicine.medical_specialty, MESH: Aorta, Thoracic, Blotting, Western, MESH : Solute Carrier Family 12, Member 2, MESH: Protein-Serine-Threonine Kinases, MESH : Angiotensin II, 03 medical and health sciences, MESH: Mice, 129 Strain, MESH: Blotting, Western, Dose-Response Relationship, Drug, MESH: Phosphorylation, MESH: Sodium-Potassium-Chloride Symporters, medicine.disease, Mice, Inbred C57BL, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, Endocrinology, Blood pressure, Vasoconstriction, MESH: Adrenergic alpha-1 Receptor Agonists, MESH: Female, MESH: Receptors, Adrenergic, alpha-1, Aorta, Thoracic, MESH : Dose-Response Relationship, Drug, Haploinsufficiency, 030204 cardiovascular system & hematology, Essential hypertension, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, Norepinephrine, WNK Lysine-Deficient Protein Kinase 1, MESH: Reverse Transcriptase Polymerase Chain Reaction, Solute Carrier Family 12, Member 2, Vasoconstrictor Agents, MESH : Female, Phosphorylation, Receptor, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Reabsorption, Angiotensin II, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Carotid Arteries, Female, MESH: Solute Carrier Family 12, Member 2, MESH: Angiotensin II, medicine.symptom, Signal transduction, MESH : Sodium-Potassium-Chloride Symporters, MESH : Adrenergic alpha-1 Receptor Agonists, MESH : Protein-Serine-Threonine Kinases, Mice, 129 Strain, MESH : Receptors, Adrenergic, alpha-1, Sodium-Potassium-Chloride Symporters, MESH : Male, Myogenic contraction, MESH : Mice, Inbred C57BL, In Vitro Techniques, Protein Serine-Threonine Kinases, Biology, Minor Histocompatibility Antigens, MESH: Vasoconstrictor Agents, MESH: Mice, Inbred C57BL, Receptors, Adrenergic, alpha-1, Internal medicine, MESH: Norepinephrine, MESH : Mice, MESH : Blood Pressure, Internal Medicine, medicine, Animals, MESH: Mice, MESH : Aorta, Thoracic, 030304 developmental biology, MESH: Carotid Arteries, MESH: Male, MESH : Phenylephrine, MESH : Mice, Knockout, Adrenergic alpha-1 Receptor Agonists, MESH : Animals, Ex vivo
Abstract

Gain-of-function mutations in the human WNK1 ( with-no-lysine[K]1 ) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1 +/− haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1 +/− mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α 1 -adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1 +/− arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na + -K + -2Cl − cotransporter 1) in Wnk1 +/− arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α 1 -adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α 1 -adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.

Published
2011
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11. A Computational Model of the Circulating Renin-Angiotensin System and Blood Pressure Regulation

Author

François Guillaud, Patrick Hannaert, Ischémie - Reperfusion en transplatation rénale, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers

Subjects
MESH: Models, Cardiovascular, Sympathetic Nervous System, MESH: Renin, Blood Pressure, 030204 cardiovascular system & hematology, Kidney, Renin-Angiotensin System, 0302 clinical medicine, MESH: Renin-Angiotensin System, Renin, MESH: Animals, MESH: Sympathetic Nervous System, General Environmental Science, 0303 health sciences, Chemistry, Angiotensin II, Systems Biology, Applied Mathematics, Models, Cardiovascular, General Medicine, MESH: Blood Pressure, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], medicine.anatomical_structure, MESH: Systems Biology, Circulatory system, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Angiotensin II, General Agricultural and Biological Sciences, Perfusion, MESH: Juxtaglomerular Apparatus, medicine.medical_specialty, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Computer Simulation, Internal medicine, Renin–angiotensin system, medicine, Animals, Humans, Computer Simulation, 030304 developmental biology, MESH: Sodium, Dietary, MESH: Humans, MESH: Models, Biological, Sodium, Dietary, Juxtaglomerular apparatus, MESH: Kidney, Juxtaglomerular Apparatus, Philosophy, Endocrinology, Blood pressure, Macula densa
Abstract

The renin-angiotensin system (RAS) is critical in sodium and blood pressure (BP) regulation, and in cardiovascular-renal (CVR) diseases and therapeutics. As a contribution to SAPHIR project, we present a realistic computer model of renin production and circulating RAS, integrated into Guyton’s circulatory model (GCM). Juxtaglomerular apparatus, JGA, and Plasma modules were implemented in C ++/M2SL (Multi-formalism Multi-resolution Simulation Library) for fusion with GCM. Matlab© optimization toolboxes were used for parameter identification. In JGA, renin production and granular cells recruitment (GCR) are controlled by perfusion pressure (PP), macula densa (MD), angiotensin II (Ang II), and renal sympathetic activity (RSNA). In Plasma, renin and ACE (angiotensin-converting enzyme) activities are integrated to yield Ang I and II. Model vs. data deviation is given as normalized root mean squared error (nRMSE; n points). Identification: JGA and Plasma parameters were identified against selected experimental data. After fusion with GCM: (1) GCR parameters were identified against Laragh’s PRA-natriuresis nomogram; (2) Renin production parameters were identified against two sets of data ([renin] transients vs. ACE or renin inhibition). Finally, GCR parameters were re-identified vs. Laragh’s nomogram (nRMSE 8%, n = 9). Validation: (1) model BP, PRA and [Ang II] are within reported ranges, and respond physiologically to sodium intake; (2) short-term Ang II infusion induces reported rise in BP and PRA. The modeled circulating RAS, in interaction with an integrated CVR, exhibits a realistic response to BP control maneuvers. This construction will allow for modelling hypertensive and CVR patients, including salt-sensitivity, polymorphisms, and pharmacotherapeutics.

Published
2010
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12. Differential effects of high and low steroidogenic factor-1 expression on CYP11B2 expression and aldosterone production in adrenocortical cells

Author

Yashuhiro Nakamura, Ping Ye, Enzo Lalli, William E. Rainey, Department of Physiology, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)

Subjects
Steroidogenic factor 1, Aldosterone synthase, Small interfering RNA, Steroidogenic Factor 1, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: RNA, Small Interfering, MESH: Doxycycline, RNA, Small Interfering, Aldosterone, Cells, Cultured, Doxycycline, 0303 health sciences, Adrenal cortex, Angiotensin II, MESH: Gene Expression Regulation, 3. Good health, medicine.anatomical_structure, MESH: Angiotensin II, medicine.drug, MESH: Cells, Cultured, medicine.medical_specialty, medicine.drug_class, 030209 endocrinology & metabolism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Aldosterone Synthase, Article, 03 medical and health sciences, Internal medicine, Mineralocorticoids, medicine, Cytochrome P-450 CYP11B2, Humans, Glucocorticoids, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Aldosterone, MESH: Steroidogenic Factor 1, Molecular biology, chemistry, Gene Expression Regulation, MESH: Mineralocorticoids, Mineralocorticoid, biology.protein, Adrenal Cortex, Steroid 11-beta-Hydroxylase, MESH: Adrenal Cortex, MESH: Glucocorticoids, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Steroid 11-beta-Hydroxylase
Abstract

International audience; Steroidogenic factor-1 (SF-1/Ad4BP/NR5A1) plays a major role in regulating steroidogenic enzymes. We have previously shown that SF-1 inhibits aldosterone synthase (CYP11B2) reporter gene activity. Herein, we used the H295R/TR/SF-1 adrenal cells that increase SF-1 in a doxycycline-dependent fashion. Cells were incubated with or without doxycycline to induce SF-1 and then treated with angiotensin II (Ang II). Aldosterone was measured by immunoassay. SF-1 mRNA was silenced by small interfering RNA (siRNA) by Nucleofector technology. mRNA levels were measured by real-time RT-PCR. Ang II treatment without doxycycline increased aldosterone production by 11.3-fold and CYP11B2 mRNA by 116-fold. Doxycycline treatment increased SF-1 mRNA levels by 3.7-fold and inhibited Ang II-induced aldosterone by 84%. Doxycycline treatment inhibited Ang II-stimulated CYP11B2 mRNA levels by 86%. Doxycycline decreased basal CYP11B2 promoter activity by 68%. Doxycycline inhibited Ang II stimulation by 85%. Ang II increased CYP21 mRNA expression by 4.6-fold, whereas doxycycline inhibited induction by 69%. In contrast, doxycycline treatment increased CYP11B1 mRNA by 1.7-fold in basal cells and increased Ang II induction by 3.6-fold. SF-1-specific siRNA significantly reduced SF-1 mRNA expression as compared with cells treated with control siRNA. SF-1 siRNA reversed doxycycline stimulation of CYP B1 and its inhibition of CYP11B2. However, in H295R/TR/SF-1 cells without doxycycline treatment, both CYP11B1 and CYP11B2 mRNAs were significantly decreased, suggesting that both enzymes require a minimal level of SF-1 for basal expression. In summary, SF-1 overexpression dramatically inhibited CYP11B2 expression and decreased aldosterone production. The opposing effects of SF-1 on CYP11B1 and CYP11B2 suggest that the regulation of SF-1 activity may play a role that determines the relative ability to produce mineralocorticoid and glucocorticoid.

Published
2009
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13. Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy

Author

Stéphane Doly, Burns C. Blaxall, Vincent Setola, Haythem Debbabi, Luc Maroteaux, Jean-Marie Launay, Jacques Callebert, Bertrand Mettauer, Philippe Bonnin, Fabrice Jaffré, Laurent Monassier, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Physiologie–Explorations Fonctionnelles, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche Cardiovasculaire de Lariboisiere, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies à prions et régulations cellulaires, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté des Sciences Pharmaceutiques et Biologiques-EA 3621, Régulation nerveuse de la fonction cardiovasculaire, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie, Hôpital pasteur [Colmar], Cardiovascular Research Institute, University of Rochester School of Medicine-Aab Cardiovascular Institute, This work has been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, the Université Louis Pasteur, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the Association pour la Recherche contre le Cancer, the French ministry of research (Agence Nationale pour la Recherche) and the European Union. LM's team is an 'Equipe Fondation pour la Recherche Médicale'. FJ is supported by a fellowship of Fondation pour la Recherche Médicale. BCB's lab is supported by an NIH grant HL084087., Maroteaux, Luc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Faculté des Sciences Pharmaceutiques et Biologiques-EA 3621

Subjects
Male, MESH: Signal Transduction, Angiotensin receptor, Physiology, medicine.medical_treatment, MESH: Myocytes, Cardiac, Stimulation, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, MESH: Isoproterenol, Muscle hypertrophy, MESH: Serotonin Antagonists, Mice, Norepinephrine, 0302 clinical medicine, Protein Interaction Mapping, Receptor, Serotonin, 5-HT2B, Myocytes, Cardiac, MESH: Animals, Receptor, Cells, Cultured, Mice, Knockout, 0303 health sciences, MESH: Cytokines, MESH: Middle Aged, Angiotensin II, Middle Aged, ErbB Receptors, src-Family Kinases, Cytokine, MESH: Receptor, Angiotensin, Type 1, Serotonin 5-HT2 Receptor Antagonists, Cytokines, Intercellular Signaling Peptides and Proteins, Female, Hypertrophy, Left Ventricular, Serotonin Antagonists, MESH: Angiotensin II, MESH: Hypertrophy, Left Ventricular, Signal transduction, Cardiology and Cardiovascular Medicine, Heparin-binding EGF-like Growth Factor, Signal Transduction, MESH: Cells, Cultured, Adult, medicine.medical_specialty, MESH: Myocardium, MESH: Mice, Transgenic, Mice, Transgenic, MESH: Receptor, Epidermal Growth Factor, Biology, Receptor, Angiotensin, Type 1, 03 medical and health sciences, Internal medicine, MESH: Norepinephrine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, 030304 developmental biology, Heart Failure, MESH: Humans, Myocardium, MESH: Protein Interaction Mapping, Isoproterenol, MESH: Receptor, Serotonin, 5-HT2B, MESH: Adult, Fibroblasts, MESH: Male, Endocrinology, MESH: src-Family Kinases, MESH: Fibroblasts, MESH: Heart Failure, Serotonin, MESH: Female
Abstract

By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT 2B receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT 2B receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT 2B receptor solely in cardiomyocytes, like global 5-HT 2B receptor–null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT 1 Rs and 5-HT 2B receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin- and angiotensin II–dependent cytokine production occur via a Src/heparin-binding epidermal growth factor–dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT 2B receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT 1 and 5-HT 2B receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT 2B receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.

Published
2009
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14. Aminopeptidase A inhibitors as centrally acting antihypertensive agents

Author

Yannick Marc, Catherine Llorens-Cortes, Laurence Bodineau, Cédric Claperon, Alain Frugière, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Llorens Cortes, Catherine

Subjects
medicine.medical_specialty, Angiotensin III, 030204 cardiovascular system & hematology, Pharmacology, Glutamyl Aminopeptidase, Models, Biological, MESH: Hypertension, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Aminopeptidase A, In vivo, MESH: Renin-Angiotensin System, Internal medicine, Renin–angiotensin system, medicine, Animals, MESH: Animals, MESH: Disulfides, Disulfides, Enzyme Inhibitors, Receptor, Antihypertensive Agents, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, chemistry.chemical_classification, MESH: Glutamyl Aminopeptidase, 0303 health sciences, MESH: Antihypertensive Agents, Effector, business.industry, Angiotensin II, MESH: Models, Biological, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Endocrinology, Blood pressure, Enzyme, chemistry, MESH: Enzyme Inhibitors, Hypertension, MESH: Sulfonic Acids, MESH: Angiotensin II, Sulfonic Acids, Cardiology and Cardiovascular Medicine, business
Abstract

International audience; Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.

Published
2008
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15. Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice

Author

Laurent Monassier, Fabrice Jaffré, Jacques de Champlain, Luc Maroteaux, Marc-André Laplante, Pascal Bousquet, Régulation nerveuse de la fonction cardiovasculaire, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche sur le Système Nerveux Autonome, Université de Montréal (UdeM)-Institut de Recherche Clinique-Faculté deMédecine, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was supported by the Canadian Institute for Health Research (Ottawa, Canada), Universite' Pierre et Marie Curie (Paris, France), Universite' Louis Pasteur (Strasbourg, France), Fondation de France (France), Fondation pour la Recherche Médicale (Paris, France), Association pour la Recherche contre le Cancer (Villejuif, France), and Agence Nationale pour la Recherche (France). L.M.'s team is an Equipe Fondation pour la Recherche Médicale (Paris, France)., and Maroteaux, Luc

Subjects
Indoles, MESH: Echocardiography, Doppler, MESH: Random Allocation, 030204 cardiovascular system & hematology, MESH: Superoxides, MESH: Isoproterenol, Muscle hypertrophy, MESH: Serotonin Antagonists, chemistry.chemical_compound, Mice, Random Allocation, 0302 clinical medicine, Reference Values, Superoxides, Receptor, Serotonin, 5-HT2B, 5-HT2B, MESH: Animals, Receptor, chemistry.chemical_classification, MESH: Indoles, 0303 health sciences, Oxidase test, Superoxide, Angiotensin II, MESH: Reference Values, MESH: Reactive Oxygen Species, Echocardiography, Doppler, 3. Good health, NAD(P)H oxidase, Quinolines, cardiovascular system, Serotonin Antagonists, adrenergic, MESH: Angiotensin II, hypertrophy, MESH: NADP, MESH: Quinolines, medicine.medical_specialty, cardiac, MESH: Probability, Cardiomegaly, Mice, Inbred Strains, Biology, Sensitivity and Specificity, MESH: Mice, Inbred Strains, 03 medical and health sciences, Internal medicine, Internal Medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Probability, Reactive oxygen species, Isoproterenol, MESH: Receptor, Serotonin, 5-HT2B, angiotensin, MESH: Sensitivity and Specificity, Disease Models, Animal, Endocrinology, chemistry, superoxide anion, NAD+ kinase, MESH: Cardiomegaly, MESH: Disease Models, Animal, Reactive Oxygen Species, NADP
Abstract

We established previously that 5-HT 2B receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-α through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT 2B receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT 2B receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47 phox NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT 2B receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT 2B receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT 2B receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and β-adrenergic trophic responses without significant hemodynamic alteration.

Published
2008
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16. Effect of apelin on glomerular hemodynamic function in the rat kidney

Author

Annette Hus-Citharel, Catherine Llorens-Cortes, Laurence Bodineau, Nadine Bouby, Jean-Marie Gasc, Alain Frugière, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Llorens Cortes, Catherine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Afferent arterioles, Vascular smooth muscle, MESH : RNA, Messenger, MESH : Myocytes, Smooth Muscle, Kidney Glomerulus, MESH : Receptors, Cell Surface, MESH : Arterioles, vascular regulation, Vasodilation, glomerulus, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Rats, Sprague-Dawley, MESH : Vasodilation, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Animals, MESH : Female, Receptor, MESH: Receptors, Cell Surface, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH : Diuresis, MESH : Hemodynamics, MESH : Rats, Angiotensin II, MESH: Diuresis, MESH: Myocytes, Smooth Muscle, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, Arterioles, medicine.anatomical_structure, MESH : Nitric Oxide, Nephrology, Intercellular Signaling Peptides and Proteins, MESH: Vasoconstriction, Female, MESH: Angiotensin II, MESH : Kidney Glomerulus, MESH : Vasoconstriction, MESH : Carrier Proteins, medicine.medical_specialty, MESH: Hemodynamics, MESH: Rats, MESH : Male, Myocytes, Smooth Muscle, MESH: Carrier Proteins, Receptors, Cell Surface, Nitric Oxide, Microcirculation, MESH : Angiotensin II, MESH: Vasodilation, 03 medical and health sciences, MESH: Arterioles, hemodynamic, Internal medicine, medicine, Animals, RNA, Messenger, 030304 developmental biology, Apelin receptor, MESH: RNA, Messenger, calcium, business.industry, Hemodynamics, MESH: Kidney Glomerulus, nephron, MESH: Male, MESH : Rats, Sprague-Dawley, Diuresis, Rats, MESH : Pregnancy, Endocrinology, Vasoconstriction, MESH: Nitric Oxide, MESH : Animals, business, Carrier Proteins, MESH: Female
Abstract

International audience; Apelin is a vasoactive peptide identified as the endogenous ligand of an orphan G protein-coupled receptor called APJ. Apelin and its receptor have been found in the brain and the cardiovascular system. Here we show that the apelin receptor mRNA is highly expressed in the glomeruli while its level of expression is lower in all nephron segments including collecting ducts that express vasopressin V2 receptors. Intravenous injection of apelin 17 into lactating rats induced a significant diuresis. Apelin receptor mRNA was also found in endothelial and vascular smooth muscle cells of glomerular arterioles. Apelin administration caused vasorelaxation of angiotensin II-preconstricted efferent and afferent arterioles as shown by an increase in their diameter. Activation of endothelial apelin receptors caused release of nitric oxide which inhibited angiotensin II-induced rise in intracellular calcium. In addition, it appears that apelin had a direct receptor-mediated vasoconstrictive effect on vascular smooth muscle. These results show that apelin has complex effects on the pre- and post glomerular microvasculature regulating renal hemodynamics. Its role on tubular function (if any) remains to be determined.

Published
2008
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17. NOX1 deficiency protects from aortic dissection in response to angiotensin II

Author

Michela G. Schäppi, Gaëtan Gavazzi, Karl-Heinz Krause, Candice Trocmé, Christine Deffert, François Herrmann, Groupe de Recherche et d’Étude du Processus Inflammatoire (TIMC-IMAG-GREPI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Male, Aneurysm, Dissecting/ chemically induced/ prevention & control, Aorta, Thoracic/metabolism, Matrix Metalloproteinase 2/metabolism, RNA, Messenger/metabolism, Gene Expression Regulation/drug effects, Aorta, Thoracic, Blood Pressure, 030204 cardiovascular system & hematology, ddc:616.07, medicine.disease_cause, MESH: Mice, Knockout, MESH: Hypertension, NADPH Oxidase/ deficiency, Norepinephrine, Mice, 0302 clinical medicine, Vasoconstrictor Agents, MESH: Animals, MESH: NADPH Oxidase, MESH: Aneurysm, Dissecting, Aortic dissection, Mice, Knockout, 0303 health sciences, Angiotensin II, MESH: Blood Pressure, MESH: Gene Expression Regulation, 3. Good health, Aortic Aneurysm, Matrix Metalloproteinase 9, Hypertension, NADPH Oxidase 1, cardiovascular system, Matrix Metalloproteinase 2, Disease Susceptibility, MESH: Angiotensin II, Matrix Metalloproteinase 9/metabolism, medicine.medical_specialty, MESH: Aorta, Thoracic, MESH: Disease Susceptibility, Biology, Sudden death, Blood Pressure/drug effects, Norepinephrine/pharmacology, 03 medical and health sciences, MESH: Vasoconstrictor Agents, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Mice, Inbred C57BL, Internal medicine, medicine.artery, MESH: Norepinephrine, Renin–angiotensin system, Internal Medicine, medicine, Animals, RNA, Messenger, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Aorta, Tissue Inhibitor of Metalloproteinase-1, Hypertension/chemically induced, NADPH Oxidases, MESH: Matrix Metalloproteinase 9, Tissue inhibitor of metalloproteinase, medicine.disease, Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism, MESH: Male, MESH: Aortic Aneurysm, Mice, Inbred C57BL, MESH: Matrix Metalloproteinase 2, B vitamins, Aortic Dissection, Endocrinology, Gene Expression Regulation, MESH: Tissue Inhibitor of Metalloproteinase-1, Aortic Aneurysm/ chemically induced/ prevention & control, Oxidative stress
Abstract

Oxidative stress leads to vascular damage and participates in the pathomechanisms of aortic dissection and aneurysm formation. Here we study aortic dissection in mice deficient in the superoxide-generating reduced nicotinamide-adenine dinucleotide phosphate oxidase NOX1. Seven days of treatment with the hypertensive agent angiotensin II (3 mg/kg per day) led to aortic dissection in 23% of wild-type C57BL/6J mice but in only 4% of NOX1-deficient mice ( P =0.05). In contrast, treatment of wild-type C57BL/6J mice with the hypertensive agent norepinephrine (12 mg/kg per day), did not lead to aortic dissection or sudden death, suggesting that hypertension is not sufficient to cause aortic dissection. Interestingly, norepinephrine-dependent blood pressure elevations were conserved in NOX1-deficient mice, demonstrating that, different from angiotensin II, it acts through NOX1-independent hypertensive mechanisms. The resistance of NOX1-deficient mice to angiotensin II-induced aortic dissection suggests a role for NOX1-dependent alterations of the vascular wall. We, therefore, studied gene expression and protease/inhibitor equilibrium. cDNA array analysis demonstrated differential effects of angiotensin II on gene expression in wild-type and NOX1-deficient mice. Tissue inhibitor of metalloproteinase 1 was increased both on the mRNA and the protein level in aortas from NOX1-deficient mice. Thus, our results demonstrate that NOX1 is involved in the mechanisms of angiotensin II-dependent aortic dissection. As one underlying mechanism, we have identified NOX1-dependent suppression of tissue inhibitor of metalloproteinase 1 expression, which could lead to tissue damage through an altered protease/inhibitor balance.

Published
2007
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18. Functional rescue of a defective angiotensin II AT1 receptor mutant by the Mas protooncogene

Author

Laerte Oliveira, João Bosco Pesquero, Michael Bader, Ronaldo Gonçalves Silva, Antonio C.M. Paiva, Jean-Loup Bascands, Suma I. Shimuta, Edson Lucas dos Santos, Claudio M. Costa-Neto, Christiane Pecher, Joost P. Schanstra, Rosana I. Reis, Department of Biophysics, Escola Paulista de Medicina-Federal University of Sao Paulo, Department of Biochemistry and Immunology, University of São Paulo (USP), Department of Medicine, Federal University of Sao Paulo, Pharmacologie Moleculaire et Physiopathologie Renale, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biology of Peptide Hormone Group (MDC), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Simon, Marie Francoise, Universidade de São Paulo = University of São Paulo (USP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Indoles, Physiology, Clinical Biochemistry, Mutant, MESH: Cricetinae, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, Biochemistry, Polymerase Chain Reaction, Receptors, G-Protein-Coupled, Endocrinology, MESH: Cricetulus, Cricetinae, Chlorocebus aethiops, MESH: Animals, Inositol phosphate, Receptor, MESH: Inhibitory Concentration 50, chemistry.chemical_classification, MESH: Indoles, Chemistry, Angiotensin II, MESH: Models, Chemical, Transfection, Fluoresceins, MESH: Fluorescent Dyes, MESH: COS Cells, Fluorescent Antibody Technique, Direct, MESH: Receptor, Angiotensin, Type 1, COS Cells, MESH: Angiotensin II, MESH: Fluorescent Antibody Technique, Direct, MESH: Mutation, G protein, MESH: Fluoresceins, Inositol Phosphates, Molecular Sequence Data, CHO Cells, Receptor, Angiotensin, Type 1, Cellular and Molecular Neuroscience, Inhibitory Concentration 50, Cricetulus, MESH: CHO Cells, Proto-Oncogenes, Animals, Amino Acid Sequence, G protein-coupled receptor, Fluorescent Dyes, Angiotensin II receptor type 1, MESH: Molecular Sequence Data, MESH: Transfection, Cell Membrane, MESH: Polymerase Chain Reaction, Molecular biology, MESH: Cercopithecus aethiops, MESH: Inositol Phosphates, Models, Chemical, MESH: Proto-Oncogenes, Mutation, MESH: Cell Membrane
Abstract

Earlier studies with Mas protooncogene, a member of the G-protein-coupled receptor family, have proposed this gene to code for a functional AngII receptor, however further results did not confirm this assumption. In this work we investigated the hypothesis that a heterodimeration AT 1 / Mas could result in a functional interaction between both receptors. For this purpose, CHO or COS-7 cells were transfected with the wild-type AT 1 receptor, a non-functional AT 1 receptor double mutant (C18F-K20A) and Mas or with WT/ Mas and C18F-K20A/ Mas . Cells single-expressing Mas or C18F/K20A did not show any binding for AngII. The co-expression of the wild-type AT 1 receptor and Mas showed a binding profile similar to that observed for the wild-type AT 1 expressed alone. Surprisingly, the co-expression of the double mutant C18F/K20A and Mas evoked a total recovery of the binding affinity for AngII to a level similar to that obtained for the wild-type AT 1 . Functional measurements using inositol phosphate and extracellular acidification rate assays also showed a clear recovery of activity for AngII on cells co-expressing the mutant C18F/K20A and Mas . In addition, immunofluorescence analysis localized the AT 1 receptor mainly at the plasma membrane and the mutant C18F-K20A exclusively inside the cells. However, the co-expression of C18F-K20A mutant with the Mas changed the distribution pattern of the mutant, with intense signals at the plasma membrane, comparable to those observed in cells expressing the wild-type AT 1 receptor. These results support the hypothesis that Mas is able to rescue binding and functionality of the defective C18F-K20A mutant by dimerization.

Published
2007
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19. In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis

Author

Georges Dagher, Alexandre Bobard, Florence Massiera, Laurent Yvan-Charvet, Xavier Rousset, Pascal Ferré, Michèle Teboul, Gérard Ailhaud, Pascale Bossard, Annie Quignard-Boulangé, Pathologies nutritionnelles et métaboliques : obésité et diabète, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Metabolisme et Differenciation Intestinale, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Time Factors, Transcription, Genetic, medicine.medical_treatment, Angiotensinogen, Adipose tissue, Receptors, Cytoplasmic and Nuclear, White adipose tissue, 030204 cardiovascular system & hematology, MESH: Eating, Eating, Mice, 0302 clinical medicine, MESH: Cholesterol, Adipocytes, Homeostasis, Insulin, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Adiposity, Liver X Receptors, Epididymis, 0303 health sciences, Angiotensin II, Scavenger Receptors, Class B, Orphan Nuclear Receptors, DNA-Binding Proteins, Protein Transport, Cholesterol, Adipose Tissue, MESH: Homeostasis, Lipogenesis, MESH: ATP-Binding Cassette Transporters, lipids (amino acids, peptides, and proteins), MESH: Angiotensin II, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Sterol Regulatory Element Binding Protein 1, MESH: Adipose Tissue, ATP Binding Cassette Transporter 1, MESH: Triglycerides, medicine.medical_specialty, MESH: Protein Transport, MESH: Mice, Transgenic, Adipose tissue macrophages, MESH: Epididymis, MESH: Angiotensinogen, Mice, Transgenic, MESH: Insulin, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, Internal medicine, 3T3-L1 Cells, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Liver X receptor, MESH: Mice, Triglycerides, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Adiposity, MESH: Lipogenesis, MESH: Transcription, Genetic, Cell Membrane, Cholesterol, HDL, MESH: Time Factors, MESH: 3T3-L1 Cells, MESH: Male, MESH: Scavenger Receptors, Class B, Endocrinology, ATP-Binding Cassette Transporters, MESH: DNA-Binding Proteins, Lipoprotein, MESH: Cell Membrane
Abstract

Objectives— This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Methods and Results— Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Conclusions— Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.

Published
2007
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20. Participation of transmembrane proline 82 in angiotensin II AT1 receptor signal transduction

Author

Christiane Pecher, Edson Lucas dos Santos, Rosana I. Reis, João Bosco Pesquero, Jean-Loup Bascands, Claudio M. Costa-Neto, Laerte Oliveira, Joost P. Schanstra, Antonio C.M. Paiva, Simon, Marie Francoise, Department of Biochemistry and Immunology, Universidade de São Paulo = University of São Paulo (USP), Department of Biophysics (UNIFESP), Escola Paulista de Medicina, Pharmacologie Moleculaire et Physiopathologie Renale, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, MESH: Signal Transduction, Physiology, Clinical Biochemistry, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, Biochemistry, Receptors, G-Protein-Coupled, Endocrinology, MESH: Structure-Activity Relationship, Chlorocebus aethiops, MESH: Animals, Receptor, Angiotensin II, Transmembrane protein, MESH: COS Cells, Transmembrane domain, MESH: Mutagenesis, Site-Directed, MESH: Receptor, Angiotensin, Type 1, COS Cells, MESH: Angiotensin II, Signal transduction, MESH: Models, Molecular, Protein Binding, Signal Transduction, MESH: Mutation, Proline, MESH: Rats, G protein, Molecular Sequence Data, MESH: Binding, Competitive, Biology, Binding, Competitive, Models, Biological, Receptor, Angiotensin, Type 1, Structure-Activity Relationship, Cellular and Molecular Neuroscience, MESH: Computer Simulation, Animals, MESH: Protein Binding, Computer Simulation, Amino Acid Sequence, G protein-coupled receptor, Angiotensin II receptor type 1, MESH: Proline, MESH: Molecular Sequence Data, MESH: Models, Biological, MESH: Cercopithecus aethiops, Rats, Mutation, Mutagenesis, Site-Directed
Abstract

International audience; Most of the classical physiological effects of the octapeptide angiotensin II (AngII) are produced by activating the AT1 receptor which belongs to the G-protein coupled receptor family (GPCR). Peptidic GPCRs may be functionally divided in three regions: (i) extracellular domains involved in ligand binding; (ii) intracellular domains implicated in agonist-induced coupling to G protein and (iii) seven transmembrane domains (TM) involved in signal transduction. The TM regions of such receptors have peculiar characteristics such as the presence of proline residues. In this project we aimed to investigate the participation of two highly conserved proline residues (Pro82 and Pro162), located in TM II and TM IV, respectively, in AT1 receptor signal transduction. Both mutations did not cause major alterations in AngII affinity. Functional assays indicated that the P162A mutant did not influence the signal transduction. On the other hand, a potent deleterious effect of P82A mutation on signal transduction was observed. We believe that the Pro82 residue is crucial to signal transduction, although it is not possible to say yet if this is due to a direct participation or if due to a structural rearrangement of TM II. In this last hypothesis, the removal of proline residue might be correlated to a removal of a kink, which in turn can be involved in the correct positioning of residues involved in signal transduction.

Published
2007
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21. Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Author

Gervais, Marianne, Dugourd, Céline, Muller, Laurent, Ardidie, Corinne, Canton, Brigitte, Loviconi, Laetitia, Corvol, Pierre, Chneiweiss, Herve, Monnot, Catherine, York, John, Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Verlaine - Metz (UPVM), Neurobiologie pharmacologique, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Neuropharmacologie (INSERM U114), Collège de France (CdF (institution)), Mouret, Sandrine, and Collège de France - Chaire Neuropharmacologie (INSERM U114)

Subjects
MAPK/ERK pathway, Transcription, Genetic, AKT1, MESH: Cricetinae, MESH: Down-Regulation, 0302 clinical medicine, Cricetinae, MESH: Animals, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Kinase, MESH: Proto-Oncogene Proteins c-fos, Angiotensin II, Intracellular Signaling Peptides and Proteins, food and beverages, Articles, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell biology, Protein Transport, 030220 oncology & carcinogenesis, MESH: Angiotensin II, Proto-Oncogene Proteins c-fos, MESH: Mitogen-Activated Protein Kinase 3, Half-Life, Protein Binding, MESH: Cells, Cultured, MESH: Half-Life, MESH: Mitogen-Activated Protein Kinase 1, MESH: Cell Nucleus, MESH: Protein Transport, MESH: Rats, Down-Regulation, CHO Cells, Biology, MESH: Phosphoproteins, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: CHO Cells, MESH: Cell Proliferation, MESH: Intracellular Signaling Peptides and Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Protein Binding, MESH: ets-Domain Protein Elk-1, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, ets-Domain Protein Elk-1, 030304 developmental biology, Cell Nucleus, Angiotensin II receptor type 1, MESH: Humans, Cell growth, MESH: Proto-Oncogene Proteins c-akt, MESH: Transcription, Genetic, Cell Biology, Phosphoproteins, Molecular biology, Rats, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt
Abstract

International audience; Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

Published
2006
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22. Decreased blood pressure in NOX1-deficient mice

Author

Botond Banfi, Michela G. Schäppi, Gaëtan Gavazzi, François Herrmann, Karl-Heinz Krause, Christine Deffert, Laurence Fiette, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Histotechnologie et Pathologie, Institut Pasteur [Paris], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), and Institut Pasteur [Paris] (IP)

Subjects
Male, MESH: Signal Transduction, MESH: Hypotension, ddc:616.07, 030204 cardiovascular system & hematology, Inbred C57BL, Biochemistry, MESH: Mice, Knockout, Muscle, Smooth, Vascular, Muscle hypertrophy, Mice, 0302 clinical medicine, Structural Biology, NADH, NADPH Oxidoreductases, MESH: Animals, Mice, Knockout, 0303 health sciences, NADPH oxidase, MESH: NADH, NADPH Oxidoreductases, biology, Angiotensin II, Tunica Media/anatomy & histology/drug effects/pathology, NADPH Oxidase 1, Extracellular matrix, MESH: Muscle, Smooth, Vascular, MESH: Blood Pressure, Vascular/cytology, Blood Pressure/drug effects/ physiology, NOX1, Blood pressure, cardiovascular system, Muscle, Female, Smooth, MESH: Angiotensin II, Hypotension, Tunica Media, Signal Transduction, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Knockout, Biophysics, MESH: Extracellular Matrix, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Cell Proliferation, Renin–angiotensin system, Genetics, medicine, Animals, Hypotension/ metabolism, Molecular Biology, MESH: Mice, 030304 developmental biology, Cell Proliferation, Signal Transduction/physiology, Extracellular Matrix/metabolism, Cell Biology, MESH: Male, Mice, Inbred C57BL, Endocrinology, MESH: Tunica Media, Decreased blood pressure, NADH, biology.protein, Angiotensin II/pharmacology, NADPH Oxidoreductases/genetics/ metabolism, MESH: Female
Abstract

International audience; To understand the role of the superoxide-generating NADPH oxidase NOX1 in the vascular system, we have generated NOX1-deficient mice. NOX1-deficient mice had a moderately decreased basal blood pressure. In response to angiotensin II they showed an almost complete loss of the sustained blood pressure response, while the initial increase was conserved. NOX1-deficient mice showed a marked reduction in aortic media hypertrophy. Angiotensin II-induced smooth muscle cell proliferation was conserved, but there was a marked decrease in extracellular matrix accumulation. Our results establish a role for NOX1 in blood pressure regulation and vascular angiotensin II response.

Published
2006
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23. Functions of serotonin in hypoxic pulmonary vascular remodeling

Author

Jean-Marie Launay, Odile Kellermann, Luc Maroteaux, Juan Miguel Esteve, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Faculté de Pharmacie, Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, AP-HP, EA 3621, Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), and Maroteaux, Luc

Subjects
MESH: Signal Transduction, MESH : Oxygen, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Serotonin, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Anoxia, MESH: Dexfenfluramine, MESH : Models, Biological, 030204 cardiovascular system & hematology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Animals, Receptor, Hypoxia, MESH : Dexfenfluramine, 0303 health sciences, MESH : Gene Expression Regulation, Angiotensin II, General Medicine, MESH : Cell Division, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Gene Expression Regulation, 3. Good health, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, MESH : Nitric Oxide, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Cell Division, MESH: Angiotensin II, MESH: Endothelium, Vascular, Signal transduction, medicine.symptom, MESH : Protein Structure, Tertiary, Cell Division, MESH: Oxygen, Blood vessel, Signal Transduction, medicine.medical_specialty, Serotonin, MESH : Hypoxia-Inducible Factor 1, alpha Subunit, MESH : Anoxia, Biophysics, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, Nitric Oxide, Models, Biological, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, Nitric oxide, MESH : Angiotensin II, 03 medical and health sciences, Dexfenfluramine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, Humans, Protein kinase B, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, MESH : Humans, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Models, Biological, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [ SDV.GEN.GA ] Life Sciences [q-bio]/Genetics/Animal genetics, Cell Biology, Hypoxia (medical), medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Pulmonary hypertension, Protein Structure, Tertiary, Oxygen, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Endocrinology, chemistry, Gene Expression Regulation, MESH : Endothelium, Vascular, MESH: Nitric Oxide, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Serotonin, Endothelium, Vascular, MESH : Animals, [ SDV.MHEP.PSR ] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract

International audience; In lung vasculature, reversible constriction of smooth muscle cells exists in response to acute decrease in oxygen levels (hypoxia). Progressive and irreversible structural remodeling that reduces blood vessel lumen takes place in response to chronic hypoxia and results in pulmonary hypertension. Several studies have shown a role of serotonin in regulating acute and chronic hypoxic responses. In this review the contribution of serotonin, its receptors and transporter in lung hypoxic responses is discussed. Hypoxic conditions modify plasma levels of serotonin, serotonin transporter activity, and expression of 5-HT1B and 5-HT2B receptors. These appear to be required for pulmonary vascular cell proliferation, which depends on the ratio between reactive oxygen species and nitric oxide. A heterozygous mutation was identified in the 5-HT2B receptor gene of a patient who developed pulmonary hypertension after fenfluramines anorexigen treatment. This C-terminus truncated 5-HT2B mutant receptor presents lower nitric oxide coupling, and higher cell proliferation capacity than the wild-type receptor. Under low oxygen tension, cells increase the transcription of specific genes via stabilization of the transcription factor hypoxia-inducible factor (HIF)-1. Factors such as angiotensin II or thrombin that can also control HIF-1 pathway contribute to pulmonary vascular remodeling. The 5-HT2B receptor via phosphatidylinositol-3 kinase/Akt activates nuclear factor-kappaB, which is involved in the regulation of HIF-1 expression. Acontrol of HIF- 1 by 5-HT2B receptors explains why expression of pulmonary vascular remodeling factors, such as endothelin-1 or transforming growth factor-beta, which is HIF-1-alpha regulated, is not modified in hypoxic 5-HT2B receptor mutant mice. Understanding the detailed mechanisms involved in lung hypoxic responses may provide general insight into pulmonary hypertension pathogenesis.

Published
2006
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24. Tyrosine kinase and mitogen-activated protein kinase/extracellularly regulated kinase differentially regulate intracellular calcium concentration responses to angiotensin II/III and bradykinin in rat cortical thick ascending limb

Author

Annette Hus-Citharel, Catherine Llorens-Cortes, Jeannine Marchetti, Pierre Corvol, Xavier Iturrioz, Llorens Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie et pathologie expérimentale vasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MAPK/ERK pathway, Male, [SDV]Life Sciences [q-bio], Angiotensin III, MESH: Rats, Sprague-Dawley, Calcium in biology, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, [CHIM] Chemical Sciences, MESH: Animals, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, Cerebral Cortex, Mitogen-Activated Protein Kinase 1, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Kinetics, Angiotensin II, Protein-Tyrosine Kinases, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV] Life Sciences [q-bio], MESH: Enzyme Inhibitors, MESH: Calcium, MESH: Angiotensin II, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Proto-oncogene tyrosine-protein kinase Src, MESH: Mitogen-Activated Protein Kinase 1, medicine.medical_specialty, Bisindolylmaleimide, MESH: Rats, Biology, Bradykinin, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, Internal medicine, medicine, [CHIM]Chemical Sciences, Animals, Protein kinase C, 030304 developmental biology, Flavonoids, MESH: Bradykinin, MESH: Male, MESH: Cerebral Cortex, Rats, Kinetics, chemistry, Calcium, MESH: Flavonoids, 030217 neurology & neurosurgery
Abstract

International audience; The cortical thick ascending limb (CTAL) coexpresses angiotensin (Ang) II/Ang III receptor type 1A (AT(1A)-R) and bradykinin (BK) receptor type 2 (B2-R). In several cell types, these two receptors share the same signaling pathways, although their physiological functions are often opposite. In CTAL, little is known about the intracellular transduction events leading to the final physiological response induced by these two peptides. We investigated and compared in this segment the action of Ang II/III and BK on intracellular calcium concentration ([Ca2+]i) response and metabolic CO2 production, an index of Na+ transport, by using inhibitors of protein kinase C (bisindolylmaleimide), Src tyrosine kinase (herbimycin A and PP2), and MAPK/ERK (PD98059 and UO126). Ang II/III and BK (10(-7) mol/liter) released Ca2+ from the same intracellular pools but activated different Ca2+ entry pathways. Ang II/III- or BK-induced [Ca2+]i increases were similarly potentiated by bisindolylmaleimide. Herbimycin A and PP2 decreased similarly the [Ca2+]i responses induced by Ang II/III and BK. In contrast, PD98059 and UO126 affected the effects of BK to a larger extent than those of Ang II/III. Especially, the Ca2+ influx induced by BK was more strongly inhibited than that induced by Ang II/III in the presence of both compounds. The Na+ transport was inhibited by BK and stimulated by Ang II/III. The inhibitory action of BK on Na+ transport was blocked by UO126, whereas the stimulatory response of Ang II/III was potentiated by UO126 but blocked by bisindolylmaleimide. These data suggest that the inhibitory effect of BK on Na+ transport seems to be directly mediated by an increase in Ca2+ influx dependent on MAPK/ERK pathway activation. In contrast, the stimulatory effect of Ang II/III on Na+ transport is more complex and involves PKC and MAPK/ERK pathways.

Published
2006
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25. Roles of brain angiotensins II and III in thirst and sodium appetite

Author

Wendy L. Wilson, Catherine Llorens-Cortes, John W. Wright, Robert C. Speth, Joseph W. Harding, Bernard P. Roques, Department of Psychology, University of Washington [Seattle], Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology, and Research Institute in Pharmaceutical Sciences, The University of Mississippi [Oxford], Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University (WSU), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Llorens Cortes, Catherine, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Washington State University ( WSU ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Captopril, Angiotensin III, Appetite, MESH : Dose-Response Relationship, Drug, Angiotensin-Converting Enzyme Inhibitors, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Thirst, MESH: Dose-Response Relationship, Drug, Rats, Sprague-Dawley, MESH: Furosemide, 0302 clinical medicine, Methionine, Sodium Potassium Chloride Symporter Inhibitors, Furosemide, MESH: Animals, MESH : Thirst, media_common, computer.programming_language, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Chemistry, sed, MESH : Rats, General Neuroscience, Angiotensin II, MESH : Sodium Chloride, Dietary, MESH: Angiotensin-Converting Enzyme Inhibitors, Brain, MESH : Injections, Intraventricular, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Furosemide, MESH : Angiotensin-Converting Enzyme Inhibitors, MESH: Angiotensin II, medicine.symptom, MESH: Injections, Intraventricular, hormones, hormone substitutes, and hormone antagonists, medicine.drug, MESH : Appetite, medicine.medical_specialty, MESH: Rats, media_common.quotation_subject, Sodium, MESH : Male, MESH : Sulfonic Acids, MESH : Captopril, chemistry.chemical_element, MESH : Angiotensin II, 03 medical and health sciences, MESH: Brain, Internal medicine, MESH : Angiotensin III, Renin–angiotensin system, medicine, Animals, Sodium Chloride, Dietary, MESH: Sodium Chloride, Dietary, Molecular Biology, Injections, Intraventricular, MESH : Methionine, Dose-Response Relationship, Drug, MESH: Captopril, MESH : Rats, Sprague-Dawley, MESH: Male, Rats, Endocrinology, MESH : Brain, MESH: Methionine, MESH : Sodium Potassium Chloride Symporter Inhibitors, MESH: Sulfonic Acids, MESH: Thirst, MESH: Appetite, Neurology (clinical), MESH : Animals, MESH: Sodium Potassium Chloride Symporter Inhibitors, Sulfonic Acids, computer, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; The current study examined the effects of intracerebroventricular (icv) infused aminopeptidase-resistant analogs of angiotensin II (AngII) and angiotensin III (AngIII) on thirst and sodium appetite. The analogs, [D-Asp1D-Arg2]AngII and [D-Arg1]AngIII, were further protected from degradation by pretreatment with the aminopeptidase A inhibitor, EC33, or the aminopeptidase N inhibitor, PC18. Prior to icv infusions, rats were sodium depleted with furosemide, followed by the angiotensin-converting enzyme inhibitor captopril, to block endogenous angiotensin formation. Both angiotensin analogs, at either of the two doses, were capable of eliciting fluid intakes of water and 0.3 M NaCl. Water and saline intakes were increased to a similar extent by 125 and 1250 pmol of [D-Asp1D-Arg2]AngII. [D-Arg1]AngIII produced a dose-dependent increase in water intake, whereas saline intake was equivalently increased by the 125 and 1250 pmol infusions. Pretreatment with EC33 or PC18 decreased water and saline intakes in response to [D-Asp1D-Arg2]AngII, while pretreatment with PC18 altered the time course of the [D-Arg1]AngIII-induced water and saline intakes. The ability of both inhibitors to decrease, but not completely block, AngII analog-induced intakes, coupled with the altered time course of the responses induced by the AngIII analog in the presence of PC18, supports the hypothesis that both AngII and AngIII are active ligands in brain angiotensin-mediated thirst and sodium appetite. However, these results do not resolve the primary question of whether conversion of AngII to AngIII is a prerequisite to dipsogenic and salt appetite responses in the brain.

Published
2005
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26. Central effects of native urotensin II on motor activity, ventilatory movements, and heart rate in the trout Oncorhynchus mykiss

Author

Jérôme Leprince, Hubert Vaudry, Jean-Claude Le Mével, D. Mabin, Nagi Mimassi, Frédéric Lancien, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Laboratoire de Neurophysiologie, and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Pulmonary Ventilation, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, 0302 clinical medicine, Heart Rate, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, MESH: Heart Rate, 0303 health sciences, biology, Angiotensin II, General Neuroscience, Low dose, Electroencephalography, MESH: Motor Activity, Trout, medicine.anatomical_structure, MESH: Oncorhynchus mykiss, Oncorhynchus mykiss, MESH: Angiotensin II, MESH: Injections, Intraventricular, medicine.medical_specialty, Urotensins, Central nervous system, Motor Activity, 03 medical and health sciences, Internal medicine, MESH: Analysis of Variance, Heart rate, MESH: Electroencephalography, medicine, Animals, Motor activity, Molecular Biology, Injections, Intraventricular, 030304 developmental biology, Analysis of Variance, MESH: Urotensins, Dose-Response Relationship, Drug, biology.organism_classification, Endocrinology, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Rainbow trout, Neurology (clinical), Pulmonary Ventilation, Urotensin-II, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Urotensin II (UII) has been originally isolated from fish urophysis. However, in fish as in mammals, UII is also produced in brain neurons. Although UII binding sites are widely distributed in the fish central nervous system (CNS), little is known regarding its central activities. In the present study, we have investigated the effects of intracerebroventricular (ICV) administration of synthetic trout UII on the duration of motor activity (ACT; evidenced by bursts of activity on the trace of the ventilatory signal), ventilatory frequency (VF), ventilatory amplitude (VA), and heart rate (HR) in unanesthesized trout, Oncorhynchus mykiss. ICV injection of very low doses of UII (1 and 5 pmol) produced a dose-dependent increase of ACT without affecting VF, VA, or HR. At a higher dose (50 pmol), UII stimulated ACT as well as VF, VA, and HR. ICV injection of trout angiotensin II (5 pmol) did not affect ACT, VF, and VA, but provoked a robust increase in HR. These data provide the first evidence that central administration of UII stimulates motor activity in a nonmammalian vertebrate.

Published
2004
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27. A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor

Author

Anne Eichmann, Marie-Pierre Simon, Ferdinand le Noble, Roselyne Tournaire, Jacques Pouysségur, Patrick England, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique des macromolécules et de leurs interactions (Plate-forme), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Biophysique des Macromolécules et de leurs Interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UNICANCER-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Darcourt, Cecilia

Subjects
Vascular Endothelial Growth Factor A, MESH: Signal Transduction, Umbilical Veins, Angiogenesis, Peptide, Chick Embryo, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Biochemistry, 0302 clinical medicine, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, MESH: Endothelial Cells, Enzyme Inhibitors, MESH: Cell Movement, Cells, Cultured, chemistry.chemical_classification, 0303 health sciences, biology, Angiotensin II, MESH: Chick Embryo, Angiopoietin receptor, Receptor, TIE-2, MESH: Receptor, TIE-2, Cell biology, Vascular endothelial growth factor A, surgical procedures, operative, Angiopoietin-1, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, MESH: Oligopeptides, embryonic structures, cardiovascular system, Biological Assay, MESH: Angiotensin II, Signal transduction, Oligopeptides, tissues, MESH: Neovascularization, Physiologic, Signal Transduction, MESH: Cells, Cultured, Scientific Report, Neovascularization, Physiologic, MESH: Umbilical Veins, MESH: Binding, Competitive, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Biological Assay, Binding, Competitive, MESH: Mitogen-Activated Protein Kinase Kinases, Angiopoietin, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Peptide Library, Consensus Sequence, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Consensus Sequence, Peptide library, Molecular Biology, 030304 developmental biology, Mitogen-Activated Protein Kinase Kinases, MESH: Humans, MESH: Vascular Endothelial Growth Factor A, Endothelial Cells, chemistry, MESH: Angiotensin I, biology.protein, MESH: Peptide Library, sense organs, Angiotensin I
Abstract

International audience; Tie2, an endothelial cell-specific receptor kinase, has an important role in tumour angiogenesis. In an attempt to identify peptides that specifically interact with and block the Tie2 pathway, a phage-displayed peptide library was screened on a recombinant Tie2 receptor. One peptide, NLLMAAS, completely abolished the binding to Tie2 of both angiopoietin 2 and angiopoietin 1 (Ang1). We further show that NLLMAAS specifically suppresses both Ang1-induced ERK activity and migration in human umbilical endothelial cells. Moreover, in vivo, this peptide inhibits angiogenesis in the chick chorioallantoic membrane assay. NLLMAAS is the first peptide described to interact with Tie2. Our results demonstrate that it is an efficient and specific antagonist of the binding of Tie2 ligands, and suggest that this peptide or its derivates may have potential applications in the treatment of angiogenesis diseases. It also represents a potent tool to dissect the molecular mechanisms involved in the Tie2 pathway.

Published
2004
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28. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome?

Author

Florence Massiera, Michael Boschmann, Jürgen Janke, K. Gorzelniak, Michèle Teboul, Stefan Engeli, Petra Schling, Arya M. Sharma, Gérard Ailhaud, Franz-Volhard Clinical Research Center, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute for Clinical Chemistry, Regensburg, Allemagne, Université Regensburg, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Cardiovascular Obesity Research, Hamilton, Canada, and McMaster University [Hamilton, Ontario]

Subjects
MESH: Renin, Angiotensinogen, Adipose tissue, Biochemistry, MESH: Hypertension, Renin-Angiotensin System, Mice, chemistry.chemical_compound, Adipose Tissue, Brown, MESH: Renin-Angiotensin System, MESH: Metabolic Syndrome X, Adipocyte, Renin, Adipocytes, MESH: Obesity, MESH: Thermogenesis, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Metabolic Syndrome, Angiotensin II, Thermogenesis, MESH: Insulin Resistance, Adipogenesis, Hypertension, MESH: Angiotensin II, medicine.medical_specialty, MESH: Rats, MESH: Angiotensinogen, Peptidyl-Dipeptidase A, Biology, MESH: Adipose Tissue, Brown, Insulin resistance, Internal medicine, Renin–angiotensin system, medicine, Animals, Humans, Obesity, MESH: Mice, MESH: Adipocytes, Angiotensin II receptor type 1, MESH: Humans, Cell Biology, medicine.disease, Rats, MESH: Peptidyl-Dipeptidase A, Endocrinology, chemistry, Insulin Resistance, Metabolic syndrome
Abstract

International audience; Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome.

Published
2003

29. Partial characterization of angiotensin II-like material extracted from the rat brain

Author

M, Pohl, A, Carayon, R, Laguzzi, A, Nosjean, G, Simonnet, M, Hamon, J C, Legrand, F, Cesselin, Neuropsychopharmacologie moléculaire, cellulaire et fonctionnelle, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Chemical Phenomena, MESH: Rats, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Radioimmunoassay, Blood Pressure, MESH: Radioimmunoassay, MESH: Brain, Animals, MESH: Animals, MESH: Chemistry, Physical, MESH: Brain Chemistry, Brain Chemistry, MESH: Tissue Extracts, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Chemistry, Physical, Tissue Extracts, Angiotensin II, Brain, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Rats, Inbred Strains, MESH: Chemical Phenomena, MESH: Chromatography, Gel, MESH: Blood Pressure, MESH: Rats, Inbred Strains, MESH: Male, Rats, Chromatography, Gel, MESH: Angiotensin II, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Angiotensin II (ANG II)-like material was detected in acid extracts of rat brain using radio-immunoassay (RIA) and a radioreceptor assay (RRA). This material, expressed as ANG II equivalents, corresponded to 131 +/- 20 fmol/g and 33 +/- 4 pmol/g as assessed by RIA and RRA respectively. Such quantitative differences indicated that the brain material did not behave as authentic ANG II in both assays, and further chromatographic investigations confirmed this inference. In particular, gel filtration through Sephadex G-25 and TSK Spherogel 3000 SW revealed that the apparent molecular weight of ANG II-like material was much higher (approximately 5000-7000) than that of authentic ANG II. Furthermore, in contrast to the marked hypertension due to ANG II, a decrease in blood pressure (BP) was observed in rats following the systemic administration of chromatographic eluates enriched with brain ANG II-like material.

Published
1986

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