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1 Pharmacology, University of California, San Diego, La Jolla, California, United States
2 Cardiovascular Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
3 Medicine, University of California, San Diego, La Jolla, California, United States
4 Pharmacology, University of California, San Diego, San Diego, California, United States
5 Department of Medicine, University of California, San Diego, LaJolla, California, United States
6 Molecular and Cellular Neurobiology, Gunma University, Maebashi, Showamachi, Japan
7 Scripps Research Institute, United States
* To whom correspondence should be addressed. E-mail: jhbrown{at}ucsd.edu.
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 injury was examined using mice in which specific S1P receptor subtypes were deleted. Mice lacking either S1P2 or S1P3 receptors and subjected to 1 hr coronary occlusion followed by 2 hr of reperfusion developed infarcts equivalent to those of wildtype mice. However, in S1P2,3 receptor double knockout mice, infarct size following ischemia-reperfusion was increased by more than 50%. Ischemia-reperfusion leads to activation of ERK, JNK, and p38 MAP kinases however these responses were not diminished in S1P2,3 receptor knockout compared to WT mice. In contrast, activation of Akt in response to ischemia-reperfusion was markedly attenuated in S1P2,3 receptor knockout mouse hearts. Neither S1P2 nor S1P3 receptor deletion alone impaired ischemia-reperfusion induced Akt activation suggesting redundant signaling through these receptors and consistent with the finding that deletion of either receptor alone did not increase ischemia-reperfusion injury. The involvement of cardiomyocytes in S1P2 and S1P3 mediated activation of Akt was tested 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 ischemia-reperfusion damage in vivo and implicate release of S1P and receptor-mediated Akt activation in this process.
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