AMP-activated protein kinase confers protection against TNF-α-induced cardiac cell death

Girish Kewalramani, Prasanth Puthanveetil, Fang Wang, Min Suk Kim, Sylvia Deppe, Ashraf Abrahani, Dan S. Luciani, James D. Johnson, Brian Rodrigues

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

AimsAlthough a substantial role for 5′ adenosine monophosphate- activated protein kinase (AMPK) has been established in regulating cardiac metabolism, a less studied action of AMPK is its ability to prevent cardiac cell death. Using established AMPK activators like dexamethasone (DEX) or metformin (MET), the objective of the present study was to determine whether AMPK activation prevents tumour necrosis factor-alpha (TNF-α) induced apoptosis in adult rat ventricular cardiomyocytes.Methods and resultsCardiomyocytes were incubated with DEX, MET, or TNF-α for varying durations (0-12 h). TNF-α-induced cell damage was evaluated by measuring caspase-3 activity and Hoechst staining. Protein and gene estimation techniques were employed to determine the mechanisms mediating the effects of AMPK activators on TNF-α-induced cardiomyocyte apoptosis. Incubation of myocytes with TNF-α for 8 h has increased caspase-3 activation and apoptotic cell death, an effect that was abrogated by DEX and MET. The beneficial effect of DEX and MET was associated with stimulation of AMPK, which led to a rapid and sustained increase in Bad phosphorylation. This event reduced the interaction between Bad and Bcl-xL, limiting cytochrome c release and caspase-3 activation. Addition of Compound C to inhibit AMPK reduced Bad phosphorylation and prevented the beneficial effects of AMPK against TNF-α-induced cytotoxicity. ConclusionOur data demonstrate that although DEX and MET are used as anti-inflammatory agents or insulin sensitizers, respectively, their common property to phosphorylate AMPK promotes cardiomyocyte cell survival through its regulation of Bad and the mitochondrial apoptotic mechanism.

Original languageEnglish
Pages (from-to)42-53
Number of pages12
JournalCardiovascular Research
Volume84
Issue number1
DOIs
StatePublished - Oct 2009

Keywords

  • AMPK
  • Apoptosis
  • Cardiomyocyte
  • Dexamethasone
  • Metformin

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