title: AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway.
abstract: Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-α (PPARα) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARα activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARα protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARα and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARα and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARα protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARα transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARα to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China. rsmeng@live.cn
authors.forename: Rongsen
authors.initials: R
authors.lastname: Meng
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Pei
authors.forename: Aixia
authors.initials: A
authors.lastname: Zhang
authors.forename: Yutian
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xingming
authors.initials: X
authors.lastname: Cai
authors.forename: Baolin
authors.initials: B
authors.lastname: Chen
authors.forename: Guanjie
authors.initials: G
authors.lastname: Liu
authors.forename: Weiyi
authors.initials: W
authors.lastname: Mai
authors.forename: Jianrui
authors.initials: J
authors.lastname: Wei
authors.forename: Yugang
authors.initials: Y
authors.lastname: Dong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide