Abstract 16017: Metformin Protects the Heart from Systolic Overload-Induced Heart Failure Through an Ampka2 Independent Pathway
We have demonstrated that gene deletion of AMPKα2 exacerbated pressure overload-induced heart failure in mice. Conversely, studies from others have demonstrated that activation of AMPK by metformin protected the heart from stress-induced heart failure. However, metformin is also known to exert biological functions through an AMPK-independent pathway. Consequently, this study examined whether metformin exerts its cardiac protective effect through an AMPKα2-dependent pathway. We first studied the effect of gene deletion of AMPKα1 and AMPKα2 on transverse aortic constriction (TAC)-induced left ventricular (LV) hypertrophy and dysfunction. We found that AMPKα2 gene deficiency significantly exacerbated TAC-induced LV hypertrophy and LV dysfunction, while AMPKα1 gene deficiency had no effect on TAC-induced LV hypertrophy or dysfunction. These data indicate that AMPKα2 (but not AMPKα1) exerts a cardioprotective effect when the heart is exposed to chronic systolic overload. We then studied the effect of metformin on TAC-induced LV hypertrophy and dysfunction in wild type mice and in mice with AMPKα2 gene deficiency. In wild type mice, metformin significantly attenuated TAC-induced LV hypertrophy and dysfunction as indicated by significantly less increases of LV weight, lung weight and their ratio to body weight or tibia length. Metformin also significantly attenuated the TAC-induced reduction of LV ejection fraction in wild type mice, and increased the phosphorylation of myocardial AMPKα and its downstream targets. Although TAC caused significantly more LV hypertrophy and dysfunction in mice with AMPKα2 gene deficiency, to our surprise, metformin was also effective in attenuating TAC-induced LV hypertrophy, pulmonary congestion and LV dysfunction in mice with AMPKα2 gene deficiency. Our data demonstrated that AMPKα2, but not AMPKα1, protected the heart from TAC-induced LV hypertrophy and heart failure, but that the cardiac protective effect of metformin did not require AMPKα2. Our findings indicate that metformin protects the heart from pressure overload-induced LV hypertrophy and heart failure through a molecular pathway independent of AMPKα2.
- © 2011 by American Heart Association, Inc.