期刊
EXPERIMENTAL CELL RESEARCH
卷 317, 期 20, 页码 2938-2949出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2011.09.011
关键词
Ischemia/reperfusion; oxidant stress; mTOR; p38 MAPK; cell survival
资金
- Xunta de Galicia [INCITE 09 208 110 PR]
- FISss [PI080655]
- NHLBI [HL061688, HL091799]
Despite intensive study, the mechanisms regulating activation of mTOR and the consequences of that activation in the ischemic heart remain unclear. This is particularly true for the setting of ischemia/reperfusion (I/R) injury. In a mouse model of I/R injury, we observed robust mTOR activation, and its inhibition by rapamycin increased injury. Consistent with the in-vivo findings, mTOR activation was also protective in isolated cardiomyocytes exposed to two models of I/R. Moreover, we identify a novel oxidant stress-activated pathway regulating mTOR that is critically dependent on p38-MAPK and Akt. This novel p38-regulated pathway signals downstream through REDD1, Tsc2, and 14-3-3 proteins to activate mTOR and is independent of AMPK. The protective role of p38/Akt and mTOR following oxidant stress is a general phenomenon since we observed it in a wide variety of cell types. Thus we have identified a novel protective pathway in the cardiomyocyte involving p38-mediated mTOR activation. Furthermore, the p38-dependent protective pathway might be able to be selectively modulated to enhance cardio-protection while not interfering with the inhibition of the better-known detrimental p38-dependent pathways. (C) 2011 Elsevier Inc. All rights reserved.
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