12 results on '"Kathleen M. S. E. Reyskens"'
Search Results
2. Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction
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Naveed Akbar, Kathleen M. S. E. Reyskens, Muhammad S. Hussain, Ify R. Mordi, Calum Forteath, J. S. C. Arthur, U Bhalraam, Chim C. Lang, Faisel Khan, and Jill J. F. Belch
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MAPK/ERK pathway ,Male ,medicine.medical_treatment ,Vasodilation ,Cohort Studies ,chemistry.chemical_compound ,Mice ,cytokine ,Medicine ,Biology (General) ,Endothelial dysfunction ,Receptor ,Spectroscopy ,Cells, Cultured ,Mice, Knockout ,biology ,Kinase ,vascular disease ,General Medicine ,Middle Aged ,Computer Science Applications ,Chemistry ,medicine.anatomical_structure ,Cytokine ,Mitogen-activated protein kinase ,Female ,medicine.symptom ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction ,Adult ,medicine.medical_specialty ,Endothelium ,endothelium ,QH301-705.5 ,Inflammation ,Ribosomal Protein S6 Kinases, 90-kDa ,Catalysis ,Article ,Nitric oxide ,Inorganic Chemistry ,Young Adult ,Internal medicine ,Animals ,Humans ,Vascular Diseases ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Aged ,business.industry ,Vascular disease ,Organic Chemistry ,vascular biology ,medicine.disease ,MAPK ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Case-Control Studies ,biology.protein ,Endothelium, Vascular ,business - Abstract
Inflammation promotes endothelial dysfunction. Using translational vascular function testing in myocardial Infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Selective activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial function before development of significant vascular disease.Graphical Abstract
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- 2021
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3. Loss of Mef2D function enhances TLR induced IL-10 production in macrophages
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Michael J. Pattison, Rangeetha Jayaprakash Naik, J. Simon C. Arthur, and Kathleen M. S. E. Reyskens
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0301 basic medicine ,Lipopolysaccharides ,Immunology & Inflammation ,medicine.medical_treatment ,T-Lymphocytes ,Biophysics ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Cytotoxic T cell ,Animals ,Autocrine signalling ,Molecular Biology ,Gene knockout ,Cells, Cultured ,Research Articles ,Mice, Knockout ,Innate immune system ,Gene Expression & Regulation ,Chemistry ,MEF2 Transcription Factors ,Macrophages ,Toll-Like Receptors ,intracellular signaling ,Cell Biology ,mef2D ,Signaling ,Cell biology ,Interleukin-10 ,Up-Regulation ,Mice, Inbred C57BL ,Interleukin 10 ,030104 developmental biology ,Cytokine ,Knockout mouse ,Tumor necrosis factor alpha ,Inflammation Mediators ,030215 immunology - Abstract
Mef2 transcription factors comprise a family of four different isoforms that regulate a number of processes including neuronal and muscle development. While roles for Mef2C and Mef2D have been described in B-cell development their role in immunity has not been extensively studied. In innate immune cells such as macrophages, TLRs drive the production of both pro- and anti-inflammatory cytokines. IL-10 is an important anti-inflammatory cytokine produced by macrophages and it establishes an autocrine feedback loop to inhibit pro-inflammatory cytokine production. We show here that macrophages from Mef2D knockout mice have elevated levels of IL-10 mRNA induction compared with wild-type cells following LPS stimulation. The secretion of IL-10 was also higher from Mef2D knockout macrophages and this correlated to a reduction in the secretion of TNF, IL-6 and IL-12p40. The use of an IL-10 neutralising antibody showed that this reduction in pro-inflammatory cytokine production in the Mef2D knockouts was IL-10 dependent. As the IL-10 promoter has previously been reported to contain a potential binding site for Mef2D, it is possible that the binding of other Mef2 isoforms in the absence of Mef2D may result in a higher activation of the IL-10 gene. Further studies with compound Mef2 isoforms would be required to address this. We also show that Mef2D is highly expressed in the thymus, but that loss of Mef2D does not affect thymic T-cell development or the production of IFNγ from CD8 T cells.
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- 2020
4. MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins
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Rachel Toth, Christopher J. Hunter, J. Simon C. Arthur, Lucia Privitera, Judit Remenyi, Bruno G. Frenguelli, Kirsty J. Martin, Sônia A. L. Corrêa, and Kathleen M. S. E. Reyskens
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0301 basic medicine ,MSK1 ,glutamate ,neurotrophins ,CREB ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Arc/Arg3.1 ,histone H3 ,Neurotrophic factors ,Serum response factor ,Protein kinase A ,Transcription factor ,Research Articles ,biology ,Serum Response Element ,QP ,Molecular biology ,BDNF ,030104 developmental biology ,NMDA ,biology.protein ,Immediate early gene ,030217 neurology & neurosurgery ,Research Article ,Neurotrophin - Abstract
The immediate early gene activity-regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain-derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic-AMP response element-binding protein (CREB) on Ser133. However, this is not required for BDNF-induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF).
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- 2017
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5. Development of Selective Covalent Janus Kinase 3 Inhibitors
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Nathanael S. Gray, Jarrod A. Marto, Kwok-Kin Wong, Shohei Koyama, Katherine Labella, Esra A. Akbay, Li Tan, Scott B. Ficarro, Grit S. Herter-Sprie, A. Thomas Look, Liv Johannessen, Suhu Liu, Koshi Akahane, Michael J. Eck, Randall McNally, J. Simon C. Arthur, Michael J. Pattison, Kathleen M. S. E. Reyskens, and David A. Frank
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Male ,Models, Molecular ,Cell signaling ,Cell Survival ,Biological Availability ,Antineoplastic Agents ,Covalent Interaction ,Article ,Mice ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Innate immune system ,Effector ,Chemistry ,Janus kinase 3 ,Janus Kinase 3 ,Xenograft Model Antitumor Assays ,Biochemistry ,STAT protein ,Molecular Medicine ,Janus kinase - Abstract
The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.
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- 2015
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6. Identifying Inhibitors of Inflammation: A Novel High-Throughput MALDI-TOF Screening Assay for Salt-Inducible Kinases (SIKs)
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Lesley-Anne Pearson, David W. Gray, Rachel E. Heap, Anthony G. Hope, Kathleen M. S. E. Reyskens, C. James Hastie, J. Simon C. Arthur, Matthias Trost, Stuart P. McElroy, and David W. Porter
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0301 basic medicine ,kinase ,interleukin-10 ,Inflammation ,Peptide ,macrophage ,Biology ,Protein Serine-Threonine Kinases ,Mass spectrometry ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,drug discovery ,03 medical and health sciences ,salt inducible kinases ,medicine ,Humans ,high-throughput screen ,IC50 ,Protein Kinase Inhibitors ,Original Research ,mass spectrometry ,chemistry.chemical_classification ,Cell Nucleus ,Drug discovery ,Kinase ,Cellular Assay ,Molecular biology ,In vitro ,0104 chemical sciences ,3. Good health ,High-Throughput Screening Assays ,010404 medicinal & biomolecular chemistry ,Protein Transport ,030104 developmental biology ,chemistry ,MALDI TOF ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Molecular Medicine ,medicine.symptom ,Biotechnology - Abstract
Matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) mass spectrometry has become a promising alternative for high-throughput drug discovery as new instruments offer high speed, flexibility and sensitivity, and the ability to measure physiological substrates label free. Here we developed and applied high-throughput MALDI TOF mass spectrometry to identify inhibitors of the salt-inducible kinase (SIK) family, which are interesting drug targets in the field of inflammatory disease as they control production of the anti-inflammatory cytokine interleukin-10 (IL-10) in macrophages. Using peptide substrates in in vitro kinase assays, we can show that hit identification of the MALDI TOF kinase assay correlates with indirect ADP-Hunter kinase assays. Moreover, we can show that both techniques generate comparable IC50 data for a number of hit compounds and known inhibitors of SIK kinases. We further take these inhibitors to a fluorescence-based cellular assay using the SIK activity-dependent translocation of CRTC3 into the nucleus, thereby providing a complete assay pipeline for the identification of SIK kinase inhibitors in vitro and in cells. Our data demonstrate that MALDI TOF mass spectrometry is fully applicable to high-throughput kinase screening, providing label-free data comparable to that of current high-throughput fluorescence assays.
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- 2017
7. Accelerated apoptotic death and in vivo turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2
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Shuchen Gu, J. Simon C. Arthur, Michael Föller, Teresa F. Ackermann, Madhuri S. Salker, Syed M. Qadri, Kathleen M. S. E. Reyskens, Kashif Jilani, Christine Zelenak, Rosi Bissinger, Yogesh Singh, Elisabeth Lang, Florian Lang, Adrian Lupescu, Erwin Schleicher, Abul Fajol, William P. Sheffield, and Mehrdad Ghashghaeinia
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Erythrocyte Indices ,Male ,Erythrocytes ,Primary Cell Culture ,Gene Expression ,Apoptosis ,Phosphatidylserines ,Biology ,Hematocrit ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,Hemolysis ,Ribosomal Protein S6 Kinases, 90-kDa ,Article ,Hemoglobins ,Mice ,chemistry.chemical_compound ,Reticulocyte Count ,Osmotic Pressure ,In vivo ,Extracellular ,medicine ,Animals ,Humans ,Mice, Knockout ,Multidisciplinary ,Osmotic concentration ,medicine.diagnostic_test ,Erythrocyte fragility ,Phosphatidylserine ,Molecular biology ,Cell biology ,body regions ,Osmotic Fragility ,chemistry ,Female ,Ex vivo - Abstract
The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte death called eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Here, we explored whether MSK1/2 participates in the regulation of eryptosis. To this end, erythrocytes were isolated from mice lacking functional MSK1/2 (msk−/−) and corresponding wild-type mice (msk+/+). Blood count, hematocrit, hemoglobin concentration and mean erythrocyte volume were similar in both msk−/− and msk+/+ mice, but reticulocyte count was significantly increased in msk−/− mice. Cell membrane PS exposure was similar in untreated msk−/− and msk+/+ erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo such as hyperosmotic shock or energy depletion to significantly higher levels in msk−/− erythrocytes than in msk+/+ erythrocytes. Cell shrinkage following hyperosmotic shock and energy depletion, as well as hemolysis following decrease of extracellular osmolarity was more pronounced in msk−/− erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled erythrocytes from circulating blood was faster in msk−/− mice. The spleens from msk−/− mice contained a significantly greater number of PS-exposing erythrocytes than spleens from msk+/+ mice. The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice.
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- 2015
8. HIV protease inhibitors and onset of cardiovascular diseases: a central role for oxidative stress and dysregulation of the ubiquitin-proteasome system
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M. Faadiel Essop and Kathleen M. S. E. Reyskens
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Programmed cell death ,Proteasome Endopeptidase Complex ,HIV Infections ,Biology ,medicine.disease_cause ,Models, Biological ,Acquired immunodeficiency syndrome (AIDS) ,Risk Factors ,medicine ,HIV Protease Inhibitor ,Humans ,Molecular Biology ,HIV-AIDS ,chemistry.chemical_classification ,Reactive oxygen species ,Ubiquitin ,Metabolic dysfunction ,virus diseases ,Lipid metabolism ,HIV Protease Inhibitors ,Cardiovascular disease ,medicine.disease ,Antiretroviral therapy ,Oxidative Stress ,Antiretroviral treatment ,chemistry ,Proteasome ,Cardiovascular Diseases ,Ubiquitin–proteasome system ,Immunology ,Molecular Medicine ,Reactive Oxygen Species ,Oxidative stress - Abstract
The successful roll-out of highly active antiretroviral therapy (HAART) has extended life expectancy and enhanced the overall well-being of HIV-positive individuals. There are, however, increased concerns regarding HAART-mediated metabolic derangements and its potential risk for cardiovascular diseases (CVD) in the long-term. Here certain classes of antiretroviral drugs such as the HIV protease inhibitors (PIs) are strongly implicated in this process. This article largely focuses on the direct PI-linked development of cardio-metabolic complications, and reviews the inter-linked roles of oxidative stress and the ubiquitin–proteasome system (UPS) as key mediators driving this process. It is proposed that PIs trigger reactive oxygen species (ROS) production that leads to serious downstream consequences such as cell death, impaired mitochondrial function, and UPS dysregulation. Moreover, we advocate that HIV PIs may also directly lower myocardial UPS function. The attenuation of cardiac UPS can initiate transcriptional changes that contribute to perturbed lipid metabolism, thereby fueling a pro-atherogenic milieu. It may also directly alter ionic channels and interfere with electrical signaling in the myocardium. Therefore HIV PI-induced ROS together with a dysfunctional UPS elicit detrimental effects on the cardiovascular system that will eventually result in the onset of heart diseases. Thus while HIV PIs substantially improve life expectancy and quality of life in HIV-positive patients, its longer-term side-effects on the cardiovascular system should lead to a) greater clinical awareness regarding its benefit–harm paradigm, and b) the development and evaluation of novel co-treatment strategies.
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- 2013
9. The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart
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Kathleen M. S. E. Reyskens and M. Faadiel Essop
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Male ,medicine.medical_specialty ,Population ,Hemodynamics ,In Vitro Techniques ,Sudden death ,Asymptomatic ,Lopinavir ,Sudden cardiac death ,Coronary artery disease ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,education ,education.field_of_study ,Ritonavir ,business.industry ,Cardiorespiratory fitness ,Heart ,HIV Protease Inhibitors ,medicine.disease ,Virology ,Adaptation, Physiological ,Rats ,Blood pressure ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
[1] Laukkanen JA, Kurl S. Blood pressure responses during exercise testing – is up best for prognosis? Ann Med 2012;44:218–24. [2] Laukkanen JA, Jennings JR, Kauhanen J, Makikallio TH, Ronkainen K, Kurl S. Relation of systemic blood pressure to sudden cardiac death. Am J Cardiol 2012;110:378–82. [3] BurkeAP, FarbA,MalcomGT, LiangY, Smialek JE, VirmaniR. Plaque rupture and sudden death related to exertion inmenwith coronary artery disease. JAMA 1999;281:921–6. [4] Burke AP, Farb A, Malcom GT, Liang YH, Smialek JE, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276–82. [5] Frohlich ED, Apstein C, Chobanian AV, et al. The heart in hypertension. N Engl J Med 1992;327:998–1008. [6] Laukkanen JA, Makikallio TH, Rauramaa R, Kiviniemi V, Ronkainen K, Kurl S. Cardiorespiratory fitness is related to the risk of sudden cardiac death. A Populationbased follow-up study. J Am Coll Cardiol 2010;56:1476–83. [7] Fagard RH, Pardaens K, Staessen JA, Thijs L. Prognostic value of invasive hemodynamic measurement at rest and during exercise in hypertensive men. Hypertension 1996;28:31–6. [8] Weiss SA, Blumenthal RS, Sharrett AR, Redberg RF, Mora S. Exercise blood pressure and future cardiovascular death in asymptomatic individuals. Circulation 2010;121:2109–16. [9] Laukkanen JA, Makikallio TH, Rauramaa R, Kurl S. Asymptomatic ST-segment depression during exercise testing and the risk of sudden cardiac death in middleaged men. A population-based follow-up study. Eur Heart J 2009;30:558–65.
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- 2013
10. Cardio-Metabolic Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir)
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Jonathan C. Schisler, Philippe Rondeau, Arlin B. Rogers, Emmanuel Bourdon, Florence Boyer, M. Faadiel Essop, Tarryn-Lee Fisher, Cynthia Planesse, Monte S. Willis, Kathleen M. S. E. Reyskens, Wendi G. O’Connor, Stellenbosch University, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Groupe d'Etude sur l'Inflammation Chronique et l'Obésité (GEICO), and Université de La Réunion (UR)
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Male ,lcsh:Medicine ,Lopinavir/ritonavir ,HIV Infections ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Lopinavir ,0302 clinical medicine ,Antiretroviral Therapy, Highly Active ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Calcineurin ,3. Good health ,Phospholamban ,Drug Combinations ,Liver ,medicine.drug ,Research Article ,Cardiac function curve ,medicine.medical_specialty ,Proteasome Endopeptidase Complex ,Blotting, Western ,Biology ,Real-Time Polymerase Chain Reaction ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Triglycerides ,030304 developmental biology ,DNA Primers ,Analysis of Variance ,Ritonavir ,NFATC Transcription Factors ,Myocardium ,lcsh:R ,Calcium-Binding Proteins ,Cholesterol, LDL ,HIV Protease Inhibitors ,medicine.disease ,Rats ,Oxidative Stress ,Endocrinology ,Connexin 43 ,Immunology ,lcsh:Q ,Oxidative stress ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction.
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- 2013
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- View/download PDF
11. Detrimental effects of antiretroviral treatment on contractile function of the rat heart
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Kathleen M. S. E. Reyskens and M. Faadiel Essop
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business.industry ,Genetics ,Antiretroviral treatment ,Medicine ,Rat heart ,Pharmacology ,business ,Molecular Biology ,Biochemistry ,Function (biology) ,Biotechnology - Published
- 2012
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12. Cardio-metabolic effectsof HIV protease inhibitors (lopinavir/ritonavir).
- Author
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Kathleen M S E Reyskens, Tarryn-Lee Fisher, Jonathan C Schisler, Wendi G O'Connor, Arlin B Rogers, Monte S Willis, Cynthia Planesse, Florence Boyer, Philippe Rondeau, Emmanuel Bourdon, and M Faadiel Essop
- Subjects
Medicine ,Science - Abstract
Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase b and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction.
- Published
- 2013
- Full Text
- View/download PDF
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