Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2

Xin Xu, Zhongbing Lu, John Fassett, Ping Zhang, Xinli Hu, Xiaoyu Liu, Dongmin Kwak, Jingxin Li, Guangshuo Zhu, Yi Tao, Mingxiao Hou, Huan Wang, Haipeng Guo, Benoit Viollet, Edward O. McFalls, Robert J. Bache, Yingjie Chen

Research output: Contribution to journalArticle

38 Scopus citations

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) and its downstream target p-p70S6K. 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.

Original languageEnglish (US)
Pages (from-to)723-728
Number of pages6
JournalHypertension
Volume63
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • heart failure
  • hypertrophy
  • metformin
  • ortic banding

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    Xu, X., Lu, Z., Fassett, J., Zhang, P., Hu, X., Liu, X., Kwak, D., Li, J., Zhu, G., Tao, Y., Hou, M., Wang, H., Guo, H., Viollet, B., McFalls, E. O., Bache, R. J., & Chen, Y. (2014). Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2. Hypertension, 63(4), 723-728. https://doi.org/10.1161/HYPERTENSIONAHA.113.02619