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AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway

Rongsen Meng1, Zhaohui Pei, Aixia Zhang

  • 1Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China. rsmeng@live.cn

Archives of Biochemistry and Biophysics
|May 3, 2011
PubMed

Insights

Activation of adenosine monophosphate-activated protein kinase (AMPK) inhibits cardiac hypertrophy. AMPK enhances peroxisome proliferators-activated receptor-α (PPARα) activity via the ERK1/2 pathway, not p38 MAPK, to reduce heart enlargement.

Area of Science:

  • Cardiovascular Biology
  • Molecular Signaling
  • Cellular Physiology

Background:

  • Cardiac hypertrophy is a significant risk factor for heart failure.
  • Adenosine monophosphate-activated protein kinase (AMPK) activation inhibits cardiac hypertrophy.
  • The precise molecular mechanisms linking AMPK to peroxisome proliferators-activated receptor-α (PPARα) signaling in cardiac hypertrophy remain incompletely understood.

Purpose of the Study:

  • To elucidate the detailed mechanism by which AMPK regulates PPARα activity in cardiac hypertrophy.
  • To investigate the role of extracellular signal regulated protein kinase (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways in this process.

Main Methods:

  • A rat model of cardiac hypertrophy induced by transaortic constriction (TAC) was employed.
  • In vitro studies utilized phenylephrine-induced hypertrophied cardiomyocytes.
  • AICAR (AMPK activator), epidermal growth factor (EGF; ERK1/2 activator), and SB203580 (p38 inhibitor) were used.
  • Protein levels, phosphorylation status, and PPARα transcriptional activity (luciferase assay) were assessed.

Main Results:

  • AICAR treatment significantly inhibited cardiac hypertrophy in vivo and in vitro.
  • TAC induced up-regulation of phospho-ERK1/2 and phospho-p38 MAPK, and down-regulation of PPARα.
  • AICAR reversed phospho-ERK1/2 and PPARα changes, while increasing phospho-p38 MAPK.
  • EGF, but not SB203580, blocked AICAR-induced PPARα up-regulation and enhanced PPARα transcriptional activity.

Conclusions:

  • AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy.
  • This effect is mediated through the ERK1/2 signaling pathway.
  • The p38 MAPK pathway is not involved in AMPK's regulation of PPARα activity in this context.

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