Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction

Abstract

Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n-6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100 mg/kg of metformin twice daily for 14 days. lsoproterenol (100 mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dt(max) and LV dp/dt(min). The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50 mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-(x), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-0/ and lL-6. However, the lower doses of 25 and 50 mg/ kg were more effective than 100 mg/kg. Phosphoi:ylated AMPKi/ (p-AMPK) in the myocardium was significantly elevated by 25 mg/kg of metformin, slightly by 50 mg/kg, but not by 100 mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarctecl myocardium. (C) 2014 Elsevier B.V. All rights reserve.