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A novel cardioprotective p38-MAPK/mTOR pathway

Gonzalo Hernández1, Hind Lal, Miguel Fidalgo

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

Experimental Cell Research
|October 18, 2011
PubMed

Insights

mTOR activation protects the heart during ischemia/reperfusion (I/R) injury by activating a novel oxidant stress pathway involving p38-MAPK and Akt. Inhibiting mTOR worsens I/R injury, highlighting its cardioprotective role.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Stress Response

Background:

  • Mechanisms of mTOR activation and its role in ischemic heart injury are not fully understood.
  • Ischemia/reperfusion (I/R) injury is a significant clinical challenge.
  • The precise signaling pathways governing mTOR in cardiac I/R injury require elucidation.

Purpose of the Study:

  • To investigate the role of mTOR activation in cardiac I/R injury.
  • To identify novel signaling pathways regulating mTOR in response to oxidant stress.
  • To explore the potential of modulating these pathways for cardioprotection.

Main Methods:

  • Utilized a mouse model of I/R injury.
  • Studied isolated cardiomyocytes subjected to I/R conditions.
  • Investigated signaling pathways including p38-MAPK, Akt, REDD1, Tsc2, and AMPK.
  • Administered rapamycin to inhibit mTOR.

Main Results:

  • Observed robust mTOR activation during I/R injury in vivo.
  • mTOR inhibition by rapamycin exacerbated I/R injury.
  • mTOR activation demonstrated a protective effect in isolated cardiomyocytes.
  • Identified a novel oxidant stress-activated pathway regulating mTOR via p38-MAPK and Akt, independent of AMPK.
  • This pathway involves REDD1, Tsc2, and 14-3-3 proteins.

Conclusions:

  • mTOR activation is protective against cardiac I/R injury.
  • A novel p38-MAPK/Akt-dependent pathway activates mTOR in response to oxidant stress.
  • This pathway offers a potential target for selective cardioprotection, distinct from detrimental p38-dependent pathways.

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