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Sphingosine-1-phosphate receptor 1 regulates cardiac function by modulating Ca2+ sensitivity and Na+/H+ exchange and mediates protection by ischemic preconditioning
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نویسنده
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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.
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منبع
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journal of the american heart association - 2016 - دوره : 5 - شماره : 5
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چکیده
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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 αmhccre) resulted in progressive cardiomyopathy,compromised response to dobutamine,and premature death. isolated cardiomyocytes from s1p1 αmhccre 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 αmhccre 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 αmhccre 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.
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کلیدواژه
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Calcium sensitization; Heart failure; Ischemia reperfusion injury; Na+/H+ exchanger; Preconditioning; Signal transduction; Sphingosine; Sphingosine-1-phosphate
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آدرس
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institute for pathophysiology,westdeutsches herz- und gefäßzentrum,universitätsklinikum essen,essen, Germany, heart failure research center,amc,university of amsterdam, Netherlands, department of cardiology,universitätsklinikum bonn,bonn, Germany, institute for pharmakology und toxikology,münster, Germany, heart failure research center,amc,university of amsterdam, Netherlands, heart failure research center,amc,university of amsterdam, Netherlands, institute for pharmakology und toxikology,münster, Germany, institute for pharmakology und toxikology,münster, Germany, department of cardiovascular physiology,ruhr university bochum,bochum, Germany, department of cardiovascular physiology,ruhr university bochum,bochum, Germany, department of pharmacology and pharmacotherapy,amc,university of amsterdam, Netherlands, institute for pharmakology und toxikology,münster,germany,department of pharmacology and toxicology,comenius university,bratislava, Slovakia, institute for pharmakology und toxikology,münster, Germany, medizinische klinik und poliklinik c,universitatsklinikum münster,münster, Germany, medizinische klinik und poliklinik c,universitatsklinikum münster,münster, Germany, heart failure research center,amc,university of amsterdam, Netherlands, department of pharmacology and pharmacotherapy,amc,university of amsterdam, Netherlands, european institute for molecular imaging,münster, Germany, department of pharmacology and pharmacotherapy,amc,university of amsterdam, Netherlands, mrb forschungszentrum magnet-resonanz-bayern e.v.,würzburg, Germany, department of molecular biology,scripps research institute,la jolla,ca, United States, institute for pathophysiology,westdeutsches herz- und gefäßzentrum,universitätsklinikum essen,essen, Germany, european institute for molecular imaging,münster, Germany, department of pharmacology and pharmacotherapy,amc,university of amsterdam, Netherlands, department of molecular biology,scripps research institute,la jolla,ca, United States, institute for pathophysiology,westdeutsches herz- und gefäßzentrum,universitätsklinikum essen,essen, Germany
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Authors
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