Adenosine monophosphate-activated protein kinase inhibits cardiac hypertrophy through reactivating peroxisome proliferator-activated receptor-alpha signaling pathway.
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.
Meng
Rong-Sen
RS
Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China.
Pei
Zhao-Hui
ZH
Yin
Ran
R
Zhang
Cheng-Xi
CX
Chen
Bao-Lin
BL
Zhang
Yang
Y
Liu
Dan
D
Xu
An-Long
AL
Dong
Yu-Gang
YG
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D005227:Fatty Acids; D047493:PPAR alpha; D055372:AMP-Activated Protein Kinases