Sphingosine-1-Phosphate Receptor 1 Regulates Cardiac Function by Modulating Ca2+ Sensitivity and Na+/H+ Exchange and Mediates Protection by Ischemic Preconditioning

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 (S1P(1)) in vivo is unknown. Methods and Results-Cardiomyocyte-restricted deletion of S1P(1) in mice (S1P(1)(alpha MHCCre)) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P(1)(alpha 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 S1P(1). This scenario was successfully reproduced in wild-type cardiomyocytes by pharmacological inhibition of S1P(1) or sphingosine kinases. Furthermore, Sarcomere shortening of S1P(1)(alpha 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, S1P(1) mediated the inhibitory effect of exogenous sphingosine-1-phosphate on beta-adrenergic-induced cardiomyocyte contractility by inhibiting the adenylate cyclase. Furthermore, ischemic precondtioning was abolished in S1P(1)(alpha MHCCre) mice and was accompanied by defective Akt activation during preconditioning. Conclusions-Tonic S1P(1) 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 S1P(1) signaling. These key findings on S1P(1) functions in cardiac physiology may offer novel therapeutic approaches to cardiac diseases.