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https://doi.org/10.1161/JAHA.116.003393
Title: | Sphingosine-1-phosphate receptor 1 regulates cardiac function by modulating Ca2+ sensitivity and Na+/H+ exchange and mediates protection by ischemic preconditioning | Authors: | Keul, P van Borren, M.M.G.J Ghanem, A Müller, F.U Baartscheer, A Verkerk, A.O Stümpel, F Schulte, J.S Hamdani, N Linke, W.A van Loenen, P Matus, M Schmitz, W Stypmann, J Tiemann, K Ravesloot, J.-H Alewijnse, A.E Hermann, S Spijkers, L.J.A Hiller, K.-H Herr, D Heusch, G Schäfers, M Peters, S.L.M Chun, J Levkau, B |
Keywords: | adenylate cyclase calcium ion dobutamine myosin binding protein C myosin light chain 2 protein kinase B sodium ion sodium proton exchange protein 1 sphingosine 1 phosphate receptor sphingosine 1 phosphate receptor 1 sphingosine kinase troponin I unclassified drug adenylate cyclase calcium cardiac myosin carrier protein growth factor-activatable Na-H exchanger NHE-1 myosin light chain myosin light chain 2 myosin-binding protein C S1pr1 protein, mouse sodium proton exchange protein sphingosine 1 phosphate receptor troponin I adrenergic system animal cell animal experiment animal model animal tissue Article cardiac muscle cell cardiomyopathy cell isolation controlled study diastole enzyme activation enzyme inhibition female heart function heart infarction prevention heart muscle contractility heart muscle fiber membrane heart muscle relaxation male mouse nonhuman premature mortality priority journal protein depletion protein function protein phosphorylation proton sodium exchange regulatory mechanism reproducibility sarcomere length sodium cell level systole action potential animal antagonists and inhibitors diagnostic imaging drug effects echocardiography genetics knockout mouse metabolism myocardial ischemia reperfusion injury nuclear magnetic resonance imaging phosphorylation positron emission tomography real time polymerase chain reaction sarcomere Western blotting Action Potentials Adenylyl Cyclases Animals Blotting, Western Calcium Cardiac Myosins Cardiomyopathies Carrier Proteins Echocardiography Ischemic Preconditioning, Myocardial Magnetic Resonance Imaging Mice Mice, Knockout Myocardial Reperfusion Injury Myocytes, Cardiac Myosin Light Chains Phosphorylation Positron-Emission Tomography Real-Time Polymerase Chain Reaction Receptors, Lysosphingolipid Sarcomeres Sodium-Hydrogen Exchangers Troponin I |
Issue Date: | 2016 | Citation: | Keul, P, van Borren, M.M.G.J, Ghanem, A, Müller, F.U, Baartscheer, A, Verkerk, A.O, Stümpel, F, Schulte, J.S, Hamdani, N, Linke, W.A, van Loenen, P, Matus, M, Schmitz, W, Stypmann, J, Tiemann, K, Ravesloot, J.-H, Alewijnse, A.E, Hermann, S, Spijkers, L.J.A, Hiller, K.-H, Herr, D, Heusch, G, Schäfers, M, Peters, S.L.M, Chun, J, Levkau, B (2016). Sphingosine-1-phosphate receptor 1 regulates cardiac function by modulating Ca2+ sensitivity and Na+/H+ exchange and mediates protection by ischemic preconditioning. Journal of the American Heart Association 5 (5) : e003393. ScholarBank@NUS Repository. https://doi.org/10.1161/JAHA.116.003393 | Rights: | Attribution 4.0 International | Abstract: | Background--Sphingosine-1-phosphate plays vital roles in cardiomyocyte physiology, myocardial ischemia-reperfusion injury, and ischemic preconditioning. The function of the cardiomyocyte sphingosine-1-phosphate receptor 1 (S1P1) in vivo is unknown. Methods and Results--Cardiomyocyte-restricted deletion of S1P1 in mice (S1P1 ?MHCCre) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P1 ?MHCCre mice revealed reduced diastolic and systolic Ca2+ concentrations that were secondary to reduced intracellular Na+ and caused by suppressed activity of the sarcolemmal Na+/H+ exchanger NHE-1 in the absence of S1P1. This scenario was successfully reproduced in wild-type cardiomyocytes by pharmacological inhibition of S1P1 or sphingosine kinases. Furthermore, Sarcomere shortening of S1P1 ?MHCCre cardiomyocytes was intact, but sarcomere relaxation was attenuated and Ca2+ sensitivity increased, respectively. This went along with reduced phosphorylation of regulatory myofilament proteins such as myosin light chain 2, myosin-binding protein C, and troponin I. In addition, S1P1 mediated the inhibitory effect of exogenous sphingosine-1-phosphate on b-adrenergic-induced cardiomyocyte contractility by inhibiting the adenylate cyclase. Furthermore, ischemic precondtioning was abolished in S1P1 ?MHCCre mice and was accompanied by defective Akt activation during preconditioning. Conclusions--Tonic S1P1 signaling by endogenous sphingosine-1-phosphate contributes to intracellular Ca2+ homeostasis by maintaining basal NHE-1 activity and controls simultaneously myofibril Ca2+ sensitivity through its inhibitory effect on adenylate cyclase. Cardioprotection by ischemic precondtioning depends on intact S1P1 signaling. These key findings on S1P1 functions in cardiac physiology may offer novel therapeutic approaches to cardiac diseases. © 2016 The Authors. | Source Title: | Journal of the American Heart Association | URI: | https://scholarbank.nus.edu.sg/handle/10635/178907 | ISSN: | 20479980 | DOI: | 10.1161/JAHA.116.003393 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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