title: Isoproterenol instigates cardiomyocyte apoptosis and heart failure via AMPK inactivation-mediated endoplasmic reticulum stress.
abstract: A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2(-/-) mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, People's Republic of China.
authors.forename: Xiao-Zhen
authors.initials: XZ
authors.lastname: Zhuo
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Ni
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Gong
authors.forename: Xue-Hui
authors.initials: XH
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Ting-Zhong
authors.initials: TZ
authors.lastname: Wang
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.forename: Ai-Qun
authors.initials: AQ
authors.lastname: Ma
authors.forename: Ping
authors.initials: P
authors.lastname: Song
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D007545:Isoproterenol / Q000009:adverse effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D020097:Natriuretic Peptide, Brain; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol