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Exp Cell Res. 2011 Dec 10;317(20):2938-49. doi: 10.1016/j.yexcr.2011.09.011. Epub 2011 Oct 2.

A novel cardioprotective p38-MAPK/mTOR pathway.

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  • 1Department of Physiology, School of Medicine, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain. gonzalo.hernandez@usc.es


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.

Copyright © 2011 Elsevier Inc. All rights reserved.

[PubMed - indexed for MEDLINE]
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