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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
Summary
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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