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Am J Physiol Heart Circ Physiol 293: H3150-H3158, 2007. First published August 31, 2007; doi:10.1152/ajpheart.00587.2006
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Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia

Jianqing Zhang,1 Norman Honbo,1 Edward J. Goetzl,2,3 Kanu Chatterjee,2 Joel S. Karliner,1,2 and Mary O. Gray1,2

1Medical Service and Cardiology Section, Veterans Affairs Medical Center, San Francisco; and Departments of 2Medicine and 3Microbiology-Immunology, University of California, San Francisco, California

Submitted 5 June 2006 ; accepted in final form 30 August 2007

Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that serves as a key regulator of cellular differentiation and survival. Immune stimuli increase S1P synthesis and secretion by mast cells and platelets, implicating this molecule in tissue responses to injury and inflammation. Binding of S1P to Gi protein-coupled receptors activates phosphatidylinositol 3-kinase and Akt in a variety of tissues. To elucidate the mechanisms by which S1P enhances adult cardiac myocyte survival during hypoxia, we used a mouse cell culture system in which S1P1 receptors were observed to transduce signals from exogenous S1P, an S1P1 receptor antibody with agonist properties, and the pharmacological agents FTY720 and SEW2871. S1P1 receptor mRNA and protein were abundantly expressed by adult mouse cardiac myocytes. S1P-S1P1 receptor axis enhancement of myocyte survival during hypoxia was abolished by phosphatidylinositol 3-kinase inhibition. S1P1 receptor function was closely associated with activation of Akt, inactivation of GSK-3beta, and reduction of cytochrome c release from heart mitochondria. These observations highlight the importance of S1P1 receptors on ventricular myocytes as mediators of inducible resistance against cellular injury during severe hypoxic stress.

heart; lysophospholipids; ischemia; cardioprotection; mitochondria


Address for reprint requests and other correspondence: M. O. Gray, Division of Cardiology 5G1, San Francisco General Hospital, 1001 Potrero Ave., San Francisco, CA 94110 (e-mail: mgray{at}medsfgh.ucsf.edu)




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