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1Biomedical Sciences Graduate Program and Departments of 2Pharmacology and 3Medicine, University of California, San Diego, La Jolla, California; and 4Department of Molecular Biology, The Scripps Research Institute, La Jolla, California
Submitted 5 December 2006 ; accepted in final form 6 February 2007
Sphingosine 1-phosphate (S1P) is released at sites of tissue injury and effects cellular responses through activation of G protein-coupled receptors. The role of S1P in regulating cardiomyocyte survival following in vivo myocardial ischemia-reperfusion (I/R) injury was examined by using mice in which specific S1P receptor subtypes were deleted. Mice lacking either S1P2 or S1P3 receptors and subjected to 1-h coronary occlusion followed by 2 h of reperfusion developed infarcts equivalent to those of wild-type (WT) mice. However, in S1P2,3 receptor double-knockout mice, infarct size following I/R was increased by >50%. I/R leads to activation of ERK, JNK, and p38 MAP kinases; however, these responses were not diminished in S1P2,3 receptor knockout compared with WT mice. In contrast, activation of Akt in response to I/R was markedly attenuated in S1P2,3 receptor knockout mouse hearts. Neither S1P2 nor S1P3 receptor deletion alone impaired I/R-induced Akt activation, which suggests redundant signaling through these receptors and is consistent with the finding that deletion of either receptor alone did not increase I/R injury. The involvement of cardiomyocytes in S1P2 and S1P3 receptor mediated activation of Akt was tested by using cells from WT and S1P receptor knockout hearts. Akt was activated by S1P, and this was modestly diminished in cardiomyocytes from S1P2 or S1P3 receptor knockout mice and completely abolished in the S1P2,3 receptor double-knockout myocytes. Our data demonstrate that activation of S1P2 and S1P3 receptors plays a significant role in protecting cardiomyocytes from I/R damage in vivo and implicate the release of S1P and receptor-mediated Akt activation in this process.
cardioprotection; mitogen-activated kinase; G protein-coupled receptors; infarct
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