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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp086
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Sphingosine 1-phosphate receptor signalling in the heart

Christopher K. Means{dagger} and Joan Heller Brown

Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093-0636

Correspondence to: Joan Heller Brown, University of California, San Diego, Department of Pharmacology, 9500 Gilman Dr. La Jolla, CA 92093-0636, Tel: (858) 822-5858, Fax: (858) 822-0041 Jhbrown{at}ucsd.edu

The five known members of the sphingosine 1-phosphate (S1P) receptor family exhibit diverse tissue expression profiles and couple to distinct G-protein-mediated signaling pathways. S1P1, S1P2, and S1P3 receptors are all present in the heart but the ratio of these subtypes differs for the various cardiac cell types. The goal of this review is to summarize data concerning which S1P receptor subtypes regulate cardiac physiology and pathophysiology, which G-proteins and signaling pathways they couple to, and in which cell types they are expressed. The available information is based on studies using a lamentably limited set of pharmacological agonists/antagonists, but is complemented by work with S1P receptor subtype-specific knockout mice and sphingosine kinase knockout mice. In cardiac myocytes the S1P1 receptor subtype is the predominant subtype expressed, and activation of this receptor inhibits cAMP formation and antagonizes adrenergic receptor-mediated contractility. The S1P3 receptor, while expressed at lower levels, mediates the bradycardic effect of S1P agonists. Studies using knockout mice indicate that S1P2 and S1P3 receptors play a major role in mediating cardioprotection from ischemia/reperfusion injury in vivo. S1P receptors are also involved in remodeling, proliferation, and differentiation of cardiac fibroblasts, a cell type in which the S1P3 receptor predominates. Receptors for S1P are also present in endothelial and smooth muscle cells where they mediate peripheral vascular tone and endothelial responses, but the role of this regulatory system in the cardiac vasculature is unknown. Further understanding of the contributions of each cell and receptor subtype to cardiac function and pathophysiology should expedite consideration of the endogenous S1P signaling pathway as a therapeutic target for cardiovascular disease.

Time for primary review: 37 Days

{dagger} Present address: Department of Pharmacology, University of Washington, Seattle, WA 98195


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