title: Sphingosine-1-Phosphate Receptor 1 Regulates Cardiac Function by Modulating Ca2+ Sensitivity and Na+/H+ Exchange and Mediates Protection by Ischemic Preconditioning.
abstract: 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.
  
  
  
  Cardiomyocyte-restricted deletion of S1P1 in mice (S1P1 (α) (MHCC) (re)) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P1 (α) (MHCC) (re) mice revealed reduced diastolic and systolic Ca(2+) 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 (α) (MHCC) (re) cardiomyocytes was intact, but sarcomere relaxation was attenuated and Ca(2+) 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 S1P1 (α) (MHCC) (re) mice and was accompanied by defective Akt activation during preconditioning.
  
  
  
  Tonic S1P1 signaling by endogenous sphingosine-1-phosphate contributes to intracellular Ca(2+) homeostasis by maintaining basal NHE-1 activity and controls simultaneously myofibril Ca(2+) 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.
authors.affiliation: Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.affiliation: Heart Failure Research Center, AMC, University of Amsterdam, The Netherlands.
authors.forename: Marcel M G J
authors.initials: MM
authors.lastname: van Borren
authors.affiliation: Department of Cardiology, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.affiliation: Institute for Pharmakology und Toxikology, Münster, Germany.
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Müller
authors.affiliation: Heart Failure Research Center, AMC, University of Amsterdam, The Netherlands.
authors.forename: Antonius
authors.initials: A
authors.lastname: Baartscheer
authors.affiliation: Heart Failure Research Center, AMC, University of Amsterdam, The Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Institute for Pharmakology und Toxikology, Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stümpel
authors.affiliation: Institute for Pharmakology und Toxikology, Münster, Germany.
authors.forename: Jan Sebastian
authors.initials: JS
authors.lastname: Schulte
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Pharmacology & Pharmacotherapy, AMC, University of Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: van Loenen
authors.affiliation: Institute for Pharmakology und Toxikology, Münster, Germany Department of Pharmacology and Toxicology, Comenius University, Bratislava, Slovakia.
authors.forename: Marek
authors.initials: M
authors.lastname: Matus
authors.affiliation: Institute for Pharmakology und Toxikology, Münster, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.affiliation: Heart Failure Research Center, AMC, University of Amsterdam, The Netherlands.
authors.forename: Jan-Hindrik
authors.initials: JH
authors.lastname: Ravesloot
authors.affiliation: Department of Pharmacology & Pharmacotherapy, AMC, University of Amsterdam, The Netherlands.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Alewijnse
authors.affiliation: European Institute for Molecular Imaging, Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: Department of Pharmacology & Pharmacotherapy, AMC, University of Amsterdam, The Netherlands.
authors.forename: Léon J A
authors.initials: LJ
authors.lastname: Spijkers
authors.affiliation: MRB Forschungszentrum Magnet-Resonanz-Bayern e.V., Würzburg, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Hiller
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, CA.
authors.forename: Deron
authors.initials: D
authors.lastname: Herr
authors.affiliation: Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.affiliation: European Institute for Molecular Imaging, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Department of Pharmacology & Pharmacotherapy, AMC, University of Amsterdam, The Netherlands.
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, CA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, Universitätsklinikum Essen, Essen, Germany bodo.levkau@uni-due.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000200:Action Potentials; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D024722:Cardiac Myosins / Q000378:metabolism; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004452:Echocardiography; D019157:Ischemic Preconditioning, Myocardial; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics*; D012518:Sarcomeres / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D019210:Troponin I / Q000378:metabolism; D000099163:Myosin Binding Protein C
chemical_list: D000262:Adenylyl Cyclases; D002118:Calcium; D024722:Cardiac Myosins; D002352:Carrier Proteins; D018994:Myosin Light Chains; D049349:Receptors, Lysosphingolipid; D017923:Sodium-Hydrogen Exchangers; D000081025:Sphingosine-1-Phosphate Receptors; D019210:Troponin I; D000099163:Myosin Binding Protein C; C556330:S1pr1 protein, mouse; C069139:growth factor-activatable Na-H exchanger NHE-1; C107184:myosin light chain 2
keywords: Na+/H+ exchanger; calcium sensitization; heart failure; ischemia reperfusion injury; preconditioning; signal transduction; sphingosine; sphingosine‐1‐phosphate