The activation of
adenosine monophosphate (
AMP)-activated protein kinase (AMPK) has been shown to inhibit
cardiac hypertrophy, however, the mechanism remains unclear. Rat models of
cardiac hypertrophy were created with transaortic constriction (TAC) to investigate the mechanistic role of AMPK involved. RT-PCR and Western blot analyses indicated that
hypertrophy marker genes
ANP and beta-MHC expression were up-regulated in the myocardium of TAC rats. We also observed that the expressions of
peroxisome proliferator-activated receptor-alpha (
PPARalpha) and its target genes,
carnitine palmitoyl
transferase-capital I, Ukrainian (
CPT-capital I, Ukrainian) and medium-chain
acyl-COA dehydrogenases (MCAD), were down-regulated, and the
fatty acid oxidation was decreased in TAC rats. Treatment of TAC animals with
5-aminoimidazole 1 carboxamide ribonucleoside (
AICAR, 0.5 mg/g body wt), a specific activator of AMPK, inhibited
cardiac hypertrophy in TAC and reversed
PPARalpha,
CPT-I and MCAD expression and
fatty acid oxidation. Similar observations were made in hypertrophied cardiomyocytes induced by
phenylephrine in vitro. Treatment of hypertrophied cardiomyocytes with Compound C, a specific AMPK inhibitor, showed an effect opposite to that of
AICAR. The effect of
AICAR on
cardiac hypertrophy was blocked after
PPARalpha was silenced by transfection of cardiomyocytes with
PPARalpha-
siRNA.
Luciferase activity assay suggested that
AICAR elevates
PPARalpha transcriptional activity. These results indicate that AMPK plays an important role in the inhibition of
cardiac hypertrophy by activating the
PPARalpha signaling pathway.