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Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia

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 G_i 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-3, 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

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