二甲双胍通过激活 AMPK 减轻压力超负荷诱导的心肌肥厚。
Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation.
机构信息
Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
出版信息
Acta Pharmacol Sin. 2011 Jul;32(7):879-87. doi: 10.1038/aps.2010.229. Epub 2011 May 9.
AIM
To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.
METHODS
Wild type and AMPKα2 knockout (AMPKα2⁻/⁻) 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 AMPKα2⁻/⁻ 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 AMPKα2⁻/⁻ 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.
目的
确定二甲双胍在心脏肥大中的作用，并探讨其作用的可能机制。
方法
对野生型和 AMPKα2 敲除（AMPKα2⁻/⁻）同窝仔鼠进行主动脉缩窄引起的左心室压力超负荷。给予二甲双胍（200 mg·kg⁻¹·d⁻¹）治疗 6 周后，通过超声心动图和解剖及组织学方法评估心脏肥大程度。使用 Western blot 分析二甲双胍的抗肥大机制。
结果
二甲双胍可显著减轻野生型小鼠压力超负荷诱导的心脏肥大，但在 AMPKα2⁻/⁻小鼠中，二甲双胍的抗肥大作用被消除。此外，二甲双胍抑制了野生型小鼠对压力超负荷的 Akt/蛋白激酶 B（AKT）和雷帕霉素靶蛋白（mTOR）的磷酸化，但在 AMPKα2⁻/⁻小鼠中没有。
结论
长期给予二甲双胍可能减轻非糖尿病小鼠压力超负荷引起的心脏肥大，这种减轻作用高度依赖于 AMPK 的激活。这些发现可能为发生病理性心脏肥大风险的患者提供一种潜在的治疗方法。
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