Adenosine monophosphate-activated protein kinase inhibits cardiac hypertrophy through reactivating peroxisome proliferator-activated receptor-α signaling pathway

作者：Meng, Rong-Sen; Pei, Zhao-hui; Yin, Ran; Zhang, Cheng-Xi; Chen, Bao-Lin; Zhang, Yang; Liu, Dan; Xu, An-Long; Dong, Yu-Gang^*

来源：European Journal of Pharmacology, 2009, 620(1-3): 63-70.

DOI：10.1016/j.ejphar.2009.08.024

• Cardiac hypertrophy
• AICAR
• AMPK
• PPAR alpha
• Fatty acid oxidation

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. RTPCR and Western blot analyses indicated that hypertrophy marker genes ANP and beta-MHC expression were up-regulated in the myrocardium of TAC rats. We also observed that the expressions of peroxisome proliferator-activated receptor-alpha (PPAR alpha) and its target genes, carnitine palmitoyl transferase- (CPT-) 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 PPAR alpha, 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 PPAR alpha was silenced by transfection of cardiomyocytes with PPAR alpha-siRNA. Luciferase activity assay suggested that AICAR elevates PPAR alpha transcriptional activity. These results indicate that AMPK plays an important role in the inhibition of cardiac hypertrophy by activating the PPAR alpha signaling pathway.

• 出版日期2009-10-12
• 单位中山大学