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Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase ?2.


ABSTRACT: Activation of AMP-activated protein kinase (AMPK)-?2 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 AMPK?2-dependent pathway. Because the role of AMPK?1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPK?1 and AMPK?2 genes on the response to transverse aortic constriction-induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPK?2 gene knockout significantly exacerbated the degree of transverse aortic constriction-induced LV hypertrophy and dysfunction, whereas AMPK?1 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 AMPK?2 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 AMPK?1 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 AMPK?2.

SUBMITTER: Xu X 

PROVIDER: S-EPMC4026291 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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