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

Abstract

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 Giprotein-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 S1P1receptors were observed to transduce signals from exogenous S1P, an S1P1receptor antibody with agonist properties, and the pharmacological agents FTY720 and SEW2871. S1P1receptor mRNA and protein were abundantly expressed by adult mouse cardiac myocytes. S1P-S1P1receptor axis enhancement of myocyte survival during hypoxia was abolished by phosphatidylinositol 3-kinase inhibition. S1P1receptor function was closely associated with activation of Akt, inactivation of GSK-3β, and reduction of cytochrome c release from heart mitochondria. These observations highlight the importance of S1P1receptors on ventricular myocytes as mediators of inducible resistance against cellular injury during severe hypoxic stress.