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

• Published in: Journal of the American Heart Association Vol. 5; no. 5
• Main Authors: Keul, Petra, Borren, Marcel M. G. J., Ghanem, Alexander, Müller, Frank Ulrich, Baartscheer, Antonius, Verkerk, Arie O., Stümpel, Frank, Schulte, Jan Sebastian, Hamdani, Nazha, Linke, Wolfgang A., Loenen, Pieter, Matus, Marek, Schmitz, Wilhelm, Stypmann, Jörg, Tiemann, Klaus, Ravesloot, Jan‐Hindrik, Alewijnse, Astrid E., Hermann, Sven, Spijkers, Léon J. A., Hiller, Karl‐Heinz, Herr, Deron, Heusch, Gerd, Schäfers, Michael, Peters, Stephan L. M., Chun, Jerold, Levkau, Bodo
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 20.05.2016; Wiley
• Subjects: Action Potentials; Adenylyl Cyclases - metabolism; Animals; Blotting, Western; Calcium - metabolism; calcium sensitization; Cardiac Myosins - metabolism; Cardiomyopathies - diagnostic imaging; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Carrier Proteins - metabolism; Echocardiography; heart failure; ischemia reperfusion injury; Ischemic Preconditioning, Myocardial; Magnetic Resonance Imaging; Mice; Mice, Knockout; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myosin Light Chains - metabolism; Na+/H+ exchanger; Original Research; Phosphorylation; Positron-Emission Tomography; preconditioning; Real-Time Polymerase Chain Reaction; Receptors, Lysosphingolipid - antagonists & inhibitors; Receptors, Lysosphingolipid - genetics; Sarcomeres - metabolism; signal transduction; Sodium-Hydrogen Exchangers - metabolism; sphingosine; sphingosine‐1‐phosphate; Troponin I - metabolism; heart failure; Na+/H+ exchanger; calcium sensitization; signal transduction; ischemia reperfusion injury; sphingosine‐1‐phosphate; sphingosine; preconditioning
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.116.003393

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 (S1P1αMHCCre) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P1αMHCCre 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 S1P1αMHCCre 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 β‐adrenergic–induced cardiomyocyte contractility by inhibiting the adenylate cyclase. Furthermore, ischemic precondtioning was abolished in S1P1αMHCCre 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.