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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
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Sphingosine-1-Phosphate Receptor 1 Regulates Cardiac Function by Modulating Ca2+ Sensitivity and Na+/H+ Exchange and
Petra Keul1, Marcel M G J van Borren2, Alexander Ghanem3
1Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, Universitätsklinikum Essen, Essen, Germany.
Journal of the American Heart Association
|May 22, 2016
Summary
Sphingosine-1-phosphate receptor 1 (S1P1) in cardiomyocytes is crucial for calcium handling and heart function. Its absence leads to cardiomyopathy and abolishes cardioprotection from ischemic preconditioning.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Sphingosine-1-phosphate (S1P) is integral to cardiomyocyte physiology, myocardial ischemia-reperfusion injury, and ischemic preconditioning.
- The in vivo function of the cardiomyocyte sphingosine-1-phosphate receptor 1 (S1P1) remains largely unknown.
Purpose of the Study:
- To elucidate the in vivo function of cardiomyocyte S1P1 in cardiac physiology and response to injury.
- To investigate the role of S1P1 in calcium homeostasis, myofilament function, and cardioprotection.
Main Methods:
- Generated cardiomyocyte-restricted S1P1 knockout mice (S1P1 (α) (MHCC) (re)).
- Assessed cardiac function, cardiomyocyte contractility, calcium handling, and myofilament protein phosphorylation.
- Evaluated the response to dobutamine and the effects of ischemic preconditioning.
Main Results:
- S1P1 deletion caused progressive cardiomyopathy, impaired dobutamine response, and premature death.
- Lack of S1P1 reduced intracellular calcium due to suppressed Na+/H+ exchanger 1 (NHE-1) activity.
- S1P1 deletion attenuated sarcomere relaxation, increased Ca2+ sensitivity, reduced myofilament protein phosphorylation, and abolished ischemic preconditioning-induced cardioprotection.
Conclusions:
- Tonic S1P1 signaling maintains cardiomyocyte calcium homeostasis via NHE-1 activity and controls myofibril Ca2+ sensitivity.
- S1P1 is essential for cardioprotection mediated by ischemic preconditioning.
- S1P1 signaling presents a potential therapeutic target for cardiac diseases.
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