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9 results on '"Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31)"'

1. Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes

Author

Gabrielle Goldman, Marc Putterman, Fabien Guimiot, Thierry Jo Molina, Alexandre Moulin, Claudine Versaux-Botteri, Loïc Van Den Berghe, Francine Behar-Cohen, Alejandra Daruich, Eric Krejci, Matthieu P. Robert, Benoit Terris, Dominique Marchant, Christophe Klein, Maud Valensi, Laurent Jonet, Frederic Mascarelli, Dominique Bremond-Gignac, Marc Abitbol, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Hormones, facteurs de croissance et physiopathologie vasculaire, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement, vieillissement et pathologie de la rétine, Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Ophthalmology, Université de Lausanne (UNIL), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), 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 de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-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 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), MINES ParisTech - École nationale supérieure des mines de Paris, Hôpital Robert Debré, Département de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-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), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Université Paris sciences et lettres (PSL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Male, Pathology, medicine.medical_specialty, genetic structures, [SDV]Life Sciences [q-bio], Blotting, Western, Retinal Pigment Epithelium, In situ hybridization, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, SOX2, medicine, Animals, Humans, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0303 health sciences, Retina, Retinal pigment epithelium, 030305 genetics & heredity, Wnt signaling pathway, Gene Expression Regulation, Developmental, Eye Diseases, Hereditary, Immunohistochemistry, eye diseases, Sensory Systems, Rats, 3. Good health, Disease Models, Animal, Ophthalmology, medicine.anatomical_structure, Child, Preschool, Eye development, RNA, Female, sense organs, PAX6, Immunostaining
Abstract

This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes.Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues.We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels. CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/β-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.

Published
2019

2. Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response

Author

Nicole Malet, Hafid Ait-Oufella, Stéphanie Gayral, Paul Ohayon, Icia Santos-Zas, Romain Solinhac, Damien Ramel, Muriel Laffargue, Didier Carrié, Lynda Zeboudj, Jean-François Arnal, Thibault Lhermusier, Mehdi Benamar, Adrien Lupieri, Abdel Saoudi, Natalia F. Smirnova, Emilio Hirsch, 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), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Complejo Hospitalario Universitario de Santiago de Compostela, 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), Department of Genetics, Biology and Biochemistry, Université de Turin, Service de cardiologie [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Hormones, facteurs de croissance et physiopathologie vasculaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Complejo Hospitalario Universitario de Santiago de Compostela [Saint-Jacques-de-Compostelle, Espagne] (CHUS), 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), Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Chemokine, Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 030204 cardiovascular system & hematology, Phosphoinositide 3-kinase, Muscle, Smooth, Vascular, 0302 clinical medicine, Re-Epithelialization, Class Ib Phosphatidylinositol 3-Kinase, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Mice, Knockout, education.field_of_study, biology, Chemistry, 3. Good health, Cell biology, medicine.anatomical_structure, Cytokine, Smooth muscle cells, Cardiology and Cardiovascular Medicine, Signal Transduction, Endothelium, Population, Myocytes, Smooth Muscle, Cardiovascular events, 03 medical and health sciences, Interferon-gamma, Immune system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Physiology (medical), Paracrine Communication, medicine, Human Umbilical Vein Endothelial Cells, CXCL10, Animals, Humans, Immune response, education, Cell Proliferation, Wound Healing, Endothelial Cells, Chemokine CXCL10, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, biology.protein, Endothelial healing, Carotid Artery Injuries, Ex vivo
Abstract

International audience; AimsDefects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γ immune processes could restore endothelial healing and identify immune mediators responsible for these defects.Methods and resultsUsing in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγ and hematopoietic cell-specific PI3Kγ deletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγ activity correlates with a decrease in local IFNγ secretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγ suggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine.ConclusionAltogether, these findings expose an unforeseen cellular cross-talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγ and the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing.

Published
2018

3. Apelin targets gut contraction to control glucose metabolism via the brain

Author

Joel Castro, Adrian Fournel, Sophie Le-Gonidec, Philippe Valet, Anne Drougard, Patrice D. Cani, Nicholas Cenac, Nathalie Vergnolle, Claude Knauf, Alysson Marlin, Stuart M. Brierley, André Colom, Thibaut Duparc, Perrine Rousset, Bernard Masri, Alexandre Lucas, UCL - SSS/LDRI - Louvain Drug Research Institute, European Associated Laboratory NeuroMicrobiota (INSERM/UCL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hormones, facteurs de croissance et physiopathologie vasculaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition and Metabolism Research Group (LDRI), Université Catholique de Louvain (UCL), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Catholique de Louvain = Catholic University of Louvain (UCL)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Duodenum, [SDV]Life Sciences [q-bio], Gut–brain axis, Hypothalamus, Biosensing Techniques, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Carbohydrate metabolism, Nitric Oxide, GUT HORMONES, Enteric Nervous System, Neurogastroenterology, Mice, 03 medical and health sciences, Adipokines, Internal medicine, Diabetes Mellitus, medicine, Animals, Homeostasis, Telemetry, Glucose homeostasis, Obesity, ComputingMilieux_MISCELLANEOUS, GLUCOSE METABOLISM, GASTROINTESTINAL PHYSIOLOGY, Gastroenterology, Muscle, Smooth, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, Mice, Inbred C57BL, Glucose, 030104 developmental biology, Endocrinology, Intercellular Signaling Peptides and Proteins, Enteric nervous system, Gastrointestinal Motility, Muscle Contraction
Abstract

ObjectiveThe gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus.DesignWe measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose.ResultsIn normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle.ConclusionsHere, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.

Published
2017

4. The Intestinal Glucose–Apelin Cycle Controls Carbohydrate Absorption in Mice

Author

Isabelle Castan-Laurell, Bernard Masri, Estelle Wanecq, Yassine Sakar, Cédric Dray, Sylvain Galvani, Philippe Valet, Larry S. Barak, Anne Nègre-Salvayre, Robert Ducroc, Luc Garrigues, Danièle Daviaud, Bernard Monsarrat, Odile Burlet-Schiltz, Claire Vinel, 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), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Cell Biology, Duke University Medical Center, This work was funded by Inserm, Université Paris Diderot Paris 7 and Université Paul 19 Sabatier. Y.S. was a recipient of Fondation pour la Recherche Médicale (FRM)., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, [SDV]Life Sciences [q-bio], Mass Spectrometry, Intestinal absorption, Mice, Random Allocation, 0302 clinical medicine, AMP-activated protein kinase, Reference Values, Glucose homeostasis, Sodium-Glucose Transporter 1, ComputingMilieux_MISCELLANEOUS, Glucose Transporter Type 2, 0303 health sciences, Microscopy, Confocal, diabetes, biology, Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, Apelin, apelin, Intercellular Signaling Peptides and Proteins, medicine.medical_specialty, mouse model, Blotting, Western, Carbohydrates, 030209 endocrinology & metabolism, Carbohydrate metabolism, 03 medical and health sciences, Internal medicine, medicine, Animals, 030304 developmental biology, Analysis of Variance, adipokine, Hepatology, Glucose transporter, Biological Transport, Mice, Inbred C57BL, Disease Models, Animal, Glucose, Endocrinology, Intestinal Absorption, biology.protein, GLUT2, Calorie intake, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Chromatography, Liquid
Abstract

International audience; BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.

Published
2013

5. Therapeutic potential of interfering with apelin signalling

Author

Bernard Knibiehler, Loïc Van Den Berghe, S. Caroline Sorli, Bernard Masri, Yves Audigier, Hormones, facteurs de croissance et physiopathologie vasculaire, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR 31 Louis Bugnard (IFR 31), 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), 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), and Simon, Marie Francoise

Subjects
MESH: Signal Transduction, medicine.medical_specialty, Angiogenesis, MESH: Receptors, G-Protein-Coupled, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Drug Design, Receptors, G-Protein-Coupled, Internal medicine, Drug Discovery, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, ComputingMilieux_MISCELLANEOUS, Apelin receptor, G protein-coupled receptor, Pharmacology, Apelin Receptors, Matrigel, MESH: Humans, Neovascularization, Pathologic, biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, Apelin, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, Drug Design, Mitogen-activated protein kinase, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Endothelium, Vascular, Endothelium, Vascular, Signal transduction, MESH: Neovascularization, Pathologic, Signal Transduction
Abstract

International audience; The apelin receptor is a G protein-coupled receptor activated by several apelin fragments. Its tissue distribution suggests that apelin signalling is involved in a broad range of physiological functions. Endothelial cells, which express high levels of apelin receptors, respond to apelin through the phosphorylation of key intracellular effectors associated with cell proliferation and migration. In addition, apelin is a mitogen for endothelial cells and exhibits angiogenic properties in matrigel experiments. This review focuses on the therapeutic potential of apelin signalling, which is associated with pathologies that result from decreased vascularisation (ischemias) or neovascularisation (retinopathies and solid tumors).

Published
2006

6. Differential display fingerprints: new approach to characterize smooth muscle cells and human coronary atherectomy tissues

Author

Francis Bayard, Yves Glock, François Heitz, Elizabeth Caussé, Meyer Elbaz, Nelly Blaes, Jacques Puel, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de cardiologie pédiatrique, Clinique Pasteur [Toulouse], Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hormones, facteurs de croissance et physiopathologie vasculaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), 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)-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), 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), Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), IFR 31 Louis Bugnard (IFR 31), 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), 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), and Simon, Marie Francoise

Subjects
Cell type, Pathology, medicine.medical_specialty, Inflammation, Coronary Artery Disease, Biology, MESH: Phenotype, Sensitivity and Specificity, Muscle, Smooth, Vascular, MESH: Gene Expression Profiling, MESH: Reverse Transcriptase Polymerase Chain Reaction, medicine, MESH: DNA Fingerprinting, Humans, Myocyte, MESH: Coronary Artery Disease, Differential display, MESH: Humans, Reverse Transcriptase Polymerase Chain Reaction, Vascular disease, Gene Expression Profiling, General Medicine, MESH: Muscle, Smooth, Vascular, medicine.disease, DNA Fingerprinting, Phenotype, MESH: Sensitivity and Specificity, Gene expression profiling, Cell culture, medicine.symptom
Abstract

International audience; AIM OF THE STUDY: Smooth muscle cells build up the normal media and stabilize atherosclerotic lesions whereas an inflammatory component is determinant for unstable angina. Smooth muscle cells, currently identified by alpha-actin, present a phenotypic heterogeneity and alpha-actin can be reduced in pathology. We tried to characterize vascular cell types, particularly smooth muscle cells, and coronary atherosclerotic tissues, by random genes expression fingerprints. MATERIALS AND METHODS: Expression fingerprints (cDNA electrophoresis) were performed by differential display reverse transcriptase-polymerase chain reaction. Variability of fingerprints was studied for a panel of arterial muscle cell phenotypes and comparisons were made with fingerprints from other cell types (endothelial cells and macrophages). The technique was then applied to human coronary atherectomy samples compared to control human arterial (mammary) smooth muscle. RESULTS: Arterial smooth muscle cells fingerprints were overall similar whatever the cell phenotype (native contractile, dedifferentiated in culture or epithelioid). Moreover, with two primer pairs, the muscular fingerprints markedly differed from the endothelial and the monocytic fingerprints. Application of differential display to coronary atherectomy samples was feasible. Interestingly, the pathological tissues exhibited either smooth muscle-like or smooth muscle-divergent fingerprints. CONCLUSIONS: Smooth muscle cells and inflammatory cells exhibited distinct differential display fingerprint patterns. Thus, a simple expression profile of arbitrary genes provides a molecular bar code tool (pattern signature) useful to characterize vascular cell cultures or tissues. The present work proposes a method to analyze coronary atherectomy samples which estimates their whole quality, muscular versus non muscular (inflammatory), this is of interest for clinical research.

Published
2007

7. The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis

Author

Diane Damotte, Luiza M Araujo, André Herbelin, Michel Dy, Emilie Philadelphe, Elke Schneider, Michel Samson, Séverine Diem, Jordan Denizeau, Ren Zhu, Aude Aumeunier, Pierre Gourdy, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-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), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard ( IFR 31 ), 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 ) -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 ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Samson, Michel, Université de Toulouse (UT)-Université de Toulouse (UT)-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 de Toulouse (UT)-Université de Toulouse (UT)-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
MESH: Interleukin-12, MESH: Mice, Mutant Strains, MESH : Cytokines, MESH: T-Lymphocyte Subsets, Hepatitis, Animal, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Concanavalin A, MESH : Th1 Cells, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Interleukin-12 Receptor beta 1 Subunit, MESH : Concanavalin A, NOD mice, 0303 health sciences, education.field_of_study, MESH: Cytokines, MESH: Hepatitis, Animal, Natural killer T cell, Interleukin-12, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, MESH : Interleukin-12 Receptor beta 1 Subunit, Interleukin 12, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Killer Cells, Natural, MESH: Killer Cells, Natural, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Population, MESH: Concanavalin A, Biology, MESH : Interleukin-4, 03 medical and health sciences, Immune system, MESH : Mice, Interleukin-12 Receptor beta 1 Subunit, medicine, MESH : Interleukin-12, Animals, Secretion, education, MESH: Mice, Interleukin 4, 030304 developmental biology, Th1 Cells, MESH: Interleukin-4, MESH : Disease Models, Animal, Mice, Mutant Strains, MESH : T-Lymphocyte Subsets, MESH : Mice, Mutant Strains, Disease Models, Animal, MESH: Th1 Cells, Interleukin-4, MESH : Animals, MESH: Disease Models, Animal, MESH : Hepatitis, Animal, 030215 immunology
Abstract

IL-12 is essential for invariant NKT (iNKT) cells because it can maintain a functionally active population and promote a cytokine profile that is assumed to be mainly of the pro-Th1 type. We used the murine concanavalin A (Con A)-induced hepatitis model, in which iNKT cells, IL-12, IL-4, and IFN-γ are equally requisite, to reevaluate this issue. We demonstrate that IL-12 interacts directly with iNKT cells, contributes to their recruitment to the liver, and enhances their IL-4 production, which is essential for disease onset. IL-12-deficient mice were less susceptible to experimental hepatitis and their iNKT cells produced less IL-4 than their wild-type counterpart. A normal response could be restored by IL-12 injection, revealing its importance as endogenous mediator. In accordance with this observation, we found that iNKT cells expressed the IL-12R constitutively, in contrast to conventional T cells. Furthermore, the physiological relevance of our data is supported by the lower susceptibility to disease induction of NOD mice, known for their inherent functional and numerical abnormalities of iNKT cells associated with decreased iNKT cell-derived IL-4 production and low IL-12 secretion. Taken together, our findings provide the first evidence that IL-12 can enhance the immune response through increased IL-4 production by iNKT cells, underscoring once more the functional plasticity of this subset.

Published
2007

8. The Adaptor Protein Gab1 Couples the Stimulation of Vascular Endothelial Growth Factor Receptor-2 to the Activation of Phosphoinositide 3-Kinase

Author

Jean-Pierre Salles, Alexandra Montagner, Bertrand Perret, Armelle Yart, Patrick Raynal, Marie Dance, Yves Audigier, Bernard Masri, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-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), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Unité d'endocrinologie et de maladie osseuse, CHU Toulouse [Toulouse], Simon, Marie Francoise, 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
Umbilical Veins, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, [SHS]Humanities and Social Sciences, chemistry.chemical_compound, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, MESH: Adenoviridae, Cell biology, Pleckstrin homology domain, Vascular endothelial growth factor, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Human umbilical vein endothelial cell, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GRB2, MESH: Endothelium, Vascular, MESH: Enzyme Activation, MESH: Mutation, MESH: Umbilical Veins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Transfection, Adenoviridae, 03 medical and health sciences, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Protein kinase B, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, MESH: Adaptor Proteins, Signal Transducing, Adaptor Proteins, Signal Transducing, Wound Healing, Phosphoinositide 3-kinase, MESH: Humans, Binding Sites, MESH: Vascular Endothelial Growth Factor Receptor-2, MESH: Transfection, Cell Membrane, Kinase insert domain receptor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: 1-Phosphatidylinositol 3-Kinase, Vascular Endothelial Growth Factor Receptor-2, Enzyme Activation, MESH: Wound Healing, chemistry, MESH: Binding Sites, MESH: Gene Deletion, Mutation, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Endothelium, Vascular, Gene Deletion, MESH: Cell Membrane
Abstract

International audience; Phosphoinositide 3-kinase (PI3K) mediates essential functions of vascular endothelial growth factor (VEGF), including the stimulation of endothelial cell proliferation and migration. Nevertheless, the mechanisms coupling the receptor VEGFR-2 to PI3K remain obscure. We observed that the Grb2-bound adapter Gab1 is tyrosine-phosphorylated and relocated to membrane fractions upon VEGF stimulation of endothelial cells. We could detect the PI3K regulatory subunit p85 in immunoprecipitates of endogenous Gab1, and vice versa, and measure a Gab1-associated lipid kinase activity upon VEGF stimulation. Furthermore, transfection of the Gab1-YF3 mutant lacking all p85-binding sites strongly repressed PI3K activation measured in vitro. Moreover, Gab1-YF3 severely decreased the cellular amount of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) generated in response to VEGF. Furthermore, adenoviral expression of Gab1-YF3 suppressed both Akt phosphorylation and recovery of wounded human umbilical vein endothelial cell monolayers, a VEGF-dependent process involving cell migration and proliferation under PI3K control. Transfection of other Gab1 mutants, lacking Grb2-binding sites or the pleckstrin homology (PH) domain, also prevented Akt activation, further demonstrating Gab1 involvement in PI3K activation. These mutants were also used to show that interactions with both Grb2 and PtdIns(3,4,5)P3 mediate Gab1 recruitment by VEGFR-2. Importantly, Gab1 mobilization was impaired by (i) PI3K inhibitors, (ii) deletion of Gab1 PH domain, (iii) PTEN (phosphatase and tensin homolog deleted on chromosome 10) overexpression to repress PtdIns(3,4,5)P3 production, and (iv) overexpression of a competitor PH domain for PtdIns(3,4,5)P3 binding, which altogether demonstrated that PI3K is also an upstream regulator of Gab1. Gab1 thus appears as a primary actor in coupling VEGFR-2 to PI3K/Akt, recruited through an amplification loop involving PtdIns(3,4,5)P3 and its PH domain.

Published
2006

9. Apelin signalling: a promising pathway from cloning to pharmacology

Author

Bernard Knibiehler, Bernard Masri, Yves Audigier, Hormones, facteurs de croissance et physiopathologie vasculaire, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR 31 Louis Bugnard (IFR 31), 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), 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), and Simon, Marie Francoise

Subjects
Central Nervous System, MESH: Signal Transduction, MESH: Rats, MESH: Carrier Proteins, MESH: Receptors, G-Protein-Coupled, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Pharmacology, Biology, MESH: Drug Design, Cardiovascular System, Receptors, G-Protein-Coupled, Mice, Structure-Activity Relationship, Immune system, MESH: Structure-Activity Relationship, Animals, Humans, MESH: Central Nervous System, MESH: Animals, MESH: Cloning, Molecular, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cloning, Molecular, Receptor, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, G protein-coupled receptor, Apelin receptor, Apelin Receptors, MESH: Humans, MESH: Cardiovascular System, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Hedgehog signaling pathway, Rats, Apelin, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Signalling, Drug Design, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Intercellular Signaling Peptides and Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, Carrier Proteins, Signal Transduction
Abstract

International audience; The discovery of new signalling pathways is always followed by the development of pharmacological agents as drugs that can be used in the treatment of diseases resulting from a dysfunction of the signalling pathway in question. Apelin signalling plays a role in the central and peripheral regulation of the cardiovascular system, in water and food intake, and possibly in immune function. Up-regulation of ligand and receptor is also associated with pathophysiological states such as cardiac dysfunction and neovascularisation. Finally, the apelin receptor is a coreceptor for the entry of several HIV-1 and SIV strains. In view of these features, the apelin receptor constitutes a very interesting target for the design of new drugs for treating the prime causes of human mortality.

Published
2005

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