title: Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2.
abstract: Activation of AMP-activated protein kinase (AMPK)-α2 protects the heart against pressure overload-induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardioprotection acts independently of an AMPKα2-dependent pathway. Because the role of AMPKα1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPKα1 and AMPKα2 genes on the response to transverse aortic constriction-induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPKα2 gene knockout significantly exacerbated the degree of transverse aortic constriction-induced LV hypertrophy and dysfunction, whereas AMPKα1 gene knockout had no effect on the degree of transverse aortic constriction-induced LV hypertrophy and dysfunction. Administration of metformin was equally effective in attenuating transverse aortic constriction-induced LV remodeling in both wild-type and AMPKα2 knockout mice, as evidenced by reduced LV and lung weights, a preserved LV ejection fraction, and reduced phosphorylation of mammalian target of rapamycin (p-mTOR(Ser2448)) and its downstream target p-p70S6K(Thr389). These data support the notion that activation of AMPKα1 plays a negligible role in protecting the heart against the adverse effects of chronic pressure overload, and that metformin protects against adverse remodeling through a pathway that seems independent of AMPKα2.
authors.affiliation: Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Mayo Mail Cod 508, 420 Delaware St SE, Minneapolis, MN 55455. chenx106@umn.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
authors.forename: John
authors.initials: J
authors.lastname: Fassett
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.forename: Dongmin
authors.initials: D
authors.lastname: Kwak
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Tao
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Hou
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Edward O
authors.initials: EO
authors.lastname: McFalls
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D004195:Disease Models, Animal; D054143:Heart Failure, Systolic / Q000503:physiopathology* / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: aortic banding; heart failure; hypertrophy; metformin