A novel cardioprotective p38-MAPK/mTOR pathway

Academic Article

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. ¬© 2011 Elsevier Inc.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Hern√°ndez G; Lal H; Fidalgo M; Guerrero A; Zalvide J; Force T; Pombo CM
  • Start Page

  • 2938
  • End Page

  • 2949
  • Volume

  • 317
  • Issue

  • 20