Department of Physiology, School of Medicine, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain.
Exp Cell Res. 2011 Dec 10;317(20):2938-49. doi: 10.1016/j.yexcr.2011.09.011. Epub 2011 Oct 2.
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.
尽管进行了深入研究，但调节 mTOR 激活的机制以及这种激活对缺血性心脏的后果仍不清楚。在缺血/再灌注 (I/R) 损伤的情况下尤其如此。在 I/R 损伤的小鼠模型中，我们观察到 mTOR 的强烈激活，而雷帕霉素对其的抑制作用会增加损伤。与体内发现一致，mTOR 的激活在暴露于两种 I/R 模型的分离心肌细胞中也具有保护作用。此外，我们还确定了一种新的氧化应激激活途径来调节 mTOR，该途径严重依赖于 p38-MAPK 和 Akt。这条新的 p38 调节途径通过 REDD1、Tsc2 和 14-3-3 蛋白向下游传递信号，激活 mTOR，并且不依赖于 AMPK。氧化应激后 p38/Akt 和 mTOR 的保护作用是一种普遍现象，因为我们在多种细胞类型中都观察到了这一现象。因此，我们在心肌细胞中鉴定出了一种新的保护途径，涉及 p38 介导的 mTOR 激活。此外，p38 依赖性保护途径可能能够被选择性地调节，以增强心脏保护作用，而不会干扰抑制更为人熟知的有害的 p38 依赖性途径。
