A novel cardioprotective p38-MAPK/mTOR pathway

被引:75
|
作者
Hernandez, Gonzalo [2 ]
Lal, Hind [1 ]
Fidalgo, Miguel [2 ]
Guerrero, Ana [2 ]
Zalvide, Juan [2 ]
Force, Thomas [1 ]
Pombo, Celia M. [2 ]
机构
[1] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA
[2] Univ Santiago de Compostela, Sch Med, Dept Physiol, Santiago De Compostela 15705, Spain
关键词
Ischemia/reperfusion; oxidant stress; mTOR; p38; MAPK; cell survival; ACTIVATED PROTEIN-KINASE; N-TERMINAL KINASES; MYOCARDIAL-INFARCTION; MAMMALIAN TARGET; ENERGY STRESS; GENE-PRODUCTS; P70S6; KINASE; CELL-GROWTH; HEART; MTOR;
D O I
10.1016/j.yexcr.2011.09.011
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:2938 / 2949
页数:12
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