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Metformin Protects Against Systolic Overload–Induced Heart Failure Independent of AMP-Activated Protein Kinase &agr;2

Activation of AMP-activated protein kinase (AMPK)-&agr;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&agr;2-dependent pathway. Because the role of AMPK&agr;1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPK&agr;1 and AMPK&agr;2 genes on the response to transverse aortic constriction–induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPK&agr;2 gene knockout significantly exacerbated the degree of transverse aortic constriction–induced LV hypertrophy and dysfunction, whereas AMPK&agr;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&agr;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-mTORSer2448) and its downstream target p-p70S6KThr389. These data support the notion that activation of AMPK&agr;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&agr;2.