Metformin improves cardiac function in rats via activation of AMP‐activated protein kinase

Summary 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.