Metformin improves cardiac function in rats via activation of AMP-activated protein kinase
Article first published online: 27 JAN 2011
© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd
Clinical and Experimental Pharmacology and Physiology
Volume 38, Issue 2, pages 94–101, February 2011
How to Cite
Wang, X.-F., Zhang, J.-Y., Li, L., Zhao, X.-Y., Tao, H.-L. and Zhang, L. (2011), Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clinical and Experimental Pharmacology and Physiology, 38: 94–101. doi: 10.1111/j.1440-1681.2010.05470.x
- Issue published online: 27 JAN 2011
- Article first published online: 27 JAN 2011
- Accepted manuscript online: 10 DEC 2010 11:00AM EST
- Received 20 September 2010; revision 1 December 2010; accepted 6 December 2010.
- AMP-activated protein kinase;
- chronic heart failure;
- endothelial nitric oxide synthase;
- transforming growth factor-β1
1. Metformin is one of the most commonly used drugs for the treatment of Type 2 diabetes. Accumulating evidence suggests that metformin also has cardioprotective effects. In the present study, we investigated the cardioprotective effects of metformin and the mechanisms involved.
2. A rat model of chronic heart failure was established by permanent left coronary artery occlusion. Heart failure rats were randomly divided into four groups: (i) a saline-treated group given 4 mL/kg day via intragastric gavage; (ii) a metformin-treated group, given 100 mg/kg metformin once daily via intragastric gavage; (iii) a group treated with 5 mg/kg 5′-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR), an AMP-activated protein kinase (AMPK) agonist, every second day; and (iv) a group treated with 100 mg/kg per day metformin + 20 mg/kg, i.p., compound C (an AMPK antagonist). After 4 weeks treatment, echocardiography was used to assess left ventricular (LV) dimensions and function. Expression of AMPK, endothelial nitric oxide synthase (eNOS) and transforming growth factor (TGF)-β1 was determined by reverse transcription–polymerase chain reaction and western blot analysis.
3. Metformin administration significantly improved cardiac function and LV remodelling, as evidenced by increases in LV systolic pressure and LV ejection fraction and decreases in LV end-diastolic diameter and LV end-systolic diameter. These beneficial effects of metformin were associated with increased AMPK and eNOS phosphorylation, as well as reductions in insulin, TGF-β1, basic fibroblast growth factor and tumour necrosis factor-α levels in the circulation and/or myocardium.
4. The results indicate that chronic low-dose metformin confers significant cardioprotective effects against chronic heart failure by activating the AMPK–eNOS pathway.