Journal
ACTA PHARMACOLOGICA SINICA
Volume 32, Issue 7, Pages 879-887Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2010.229
Keywords
metformin; cardiac hypertrophy; AMP-activated protein kinase; protein synthesis; transverse aortic constriction; Akt/protein kinase B; mammalian target of rapamycin
Funding
- National Natural Science Foundation of China [81030001, 30821001]
- NSFC [30910103902]
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Aim: To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect. Methods: Wild type and AMPK alpha 2 knockout (AMPK alpha 2(-/-)) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg.kg(-1).d(-1)) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting. Results: Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPK alpha 2(-/-) mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPK alpha 2(-/-) mice. Conclusion: Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.
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