A novel cardioprotective p38-MAPK/mTOR pathway

Abstract

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.

Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway

“…Previously, it has been reported that mTOR inhibition by rapamycin increases infarct size at 24 h post-I/R in vivo [37]. However, previous reports have demonstrated that mTOR inhibition protected the heart in an in vivo MI model using an LAD permanent ligation without reperfusion [38,39].…”

S100A8 Induces IL-10 and Protects against Acute Lung Injury

“…Unexpectedly, S100A8 elevated pMEK1/2 pERK1/2 and p38 MAPKs in lungs harvested 4 h after LPS. pERK mediates antioxidant protection in monocytoid cells challenged by oxidative stress (47), and a novel oxidant stress-activated pathway that is protective in ischemia is dependent on p38-MAPK and p-Akt (48). Thus, activation of these may constitute part of a survival pathway mediated by S100A8.…”

High frequency electrical stimulation reveals a p38-mTOR signaling module correlated with force-time integral

“…The correlations between FTI, FAK and p38 may represent a single pathway, as a hypertrophic signaling pathway involving integrin-FAK and p38 induced by mechanical stress has been reported (Aikawa et al, 2002;Lal et al, 2007). Activation of p38 may contribute to increased protein synthesis via phosphorylation of TSC2-and MNK-induced phosphorylation of eIF4E and p70S6k on T421/S424 (Cully et al, 2010;Hernández et al, 2011;Wang et al, 1998) and is required for myogenic differentiation via activation of MEF2 and MRF4 (Lluís et al, 2006), both processes required for muscle hypertrophy. The correlation found between p38 and mTOR in both experiments is consistent with the observations in Drosophila that p38 is a positive regulator of mTOR through TSC1/2-dependent mechanisms (Cully et al, 2010), potentially by promoting interaction of TSC1/2 and 14-3-3 (Hernández et al, 2011).…”

“…Activation of p38 may contribute to increased protein synthesis via phosphorylation of TSC2-and MNK-induced phosphorylation of eIF4E and p70S6k on T421/S424 (Cully et al, 2010;Hernández et al, 2011;Wang et al, 1998) and is required for myogenic differentiation via activation of MEF2 and MRF4 (Lluís et al, 2006), both processes required for muscle hypertrophy. The correlation found between p38 and mTOR in both experiments is consistent with the observations in Drosophila that p38 is a positive regulator of mTOR through TSC1/2-dependent mechanisms (Cully et al, 2010), potentially by promoting interaction of TSC1/2 and 14-3-3 (Hernández et al, 2011). The persistence of the p38-mTOR module even under high metabolic stress in the HDC protocols suggests that activation of a force-related growth pathway can occur simultaneous with activation of AMPK.…”