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AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death

Girish Kewalramani1, Prasanth Puthanveetil, Fang Wang

  • 1Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.

Cardiovascular Research
|May 30, 2009
PubMed
Abstract

Insights

AMPK activation by dexamethasone or metformin protects adult rat ventricular cardiomyocytes from TNF-alpha-induced apoptosis by regulating the Bad protein and mitochondrial pathways, enhancing cell survival.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Death Research

Background:

  • 5' adenosine monophosphate-activated protein kinase (AMPK) is known to regulate cardiac metabolism.
  • A less-explored function of AMPK is its role in preventing cardiac cell death.

Purpose of the Study:

  • To investigate if AMPK activation prevents tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in adult rat ventricular cardiomyocytes.
  • To determine the effects of AMPK activators, dexamethasone (DEX) and metformin (MET), on TNF-alpha-induced cardiomyocyte apoptosis.

Main Methods:

  • Cardiomyocytes were treated with DEX, MET, or TNF-alpha.
  • Assessed TNF-alpha-induced cell damage via caspase-3 activity and Hoechst staining.
  • Utilized protein and gene expression techniques to elucidate the mechanisms of AMPK activators.

Main Results:

  • TNF-alpha induced caspase-3 activation and apoptosis, which was prevented by DEX and MET.
  • DEX and MET treatment stimulated AMPK, increasing Bad phosphorylation and reducing Bad-Bcl-xL interaction.
  • This led to decreased cytochrome c release and caspase-3 activation, confirming AMPK's protective role.

Conclusions:

  • Dexamethasone and metformin promote cardiomyocyte survival by activating AMPK.
  • AMPK activation phosphorylates Bad, inhibiting the mitochondrial apoptotic pathway.
  • This mechanism underlies the cardioprotective effects of these agents against TNF-alpha-induced cell death.

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