Please use this identifier to cite or link to this item: 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
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