The role of 5'-AMP-activated protein kinase (AMPK) in acute myocardial infarction remodelling

Abstract

Introduction: Metformin has been demonstrated to possess cardioprotective properties in Myocardial infarction (MI). The innate immune response through Toll like receptors (TLRs) is activated during MI. In this study, the effects of acute and sub-chronic metformin treatment on TLRs activity and its relation with AMPK in isoproterenol-induced MI were assessed in rats. Methods: Isoproterenol was injected subcutaneously at 100 mg/kg for 2 consecutive days and metformin was administered orally in three doses of 25, 50, and 100 mg/kg twice daily for 2 days in acute and for 14 days in sub-chronic pre-treatment. Results: Isoproterenol caused an intensive myocardial necrosis and fibrosis along with a profound decrease in arterial pressure indices, left ventricular contractility (LVdP/dtmax) and relaxation (LVdP/dtmin). Histopathological analysis showed a marked attenuation of myocyte necrosis and fibrosis in all metformin treated groups. Metformin at 50 mg/kg strongly (p<0.01, p<0.05) increased LVdP/dtmax from 2988±439 and 3399±380 (mmHg/sec) in the MI group in acute and sub-chronic treatment to 4699±332 and 4737±212 (mmHg/sec), respectively. Metformin also reduced inflammatory responses as indexed by reduced myocardial levels of TNFα (maximum 68%, 59% p<0.001) and IL6 (maximum 84%; 75% p<0.001) as well as myocardial myeloperoxidase (MPO) activity (25%; 55% p<0.01) in acute and sub-chronic treatment with metformin respectively. Metformin 100 mg/kg in acute treatment and 25 mg/kg in sub-chronic pre-treatment, significantly upregulated the level of phosphorylated AMPK by 165% and 185% (p<0.001), respectively. This was associated with a remarkable reduction of protein level of TLRs adapter protein, MyD88 (p<0.01, p<0.001), that was elevated (p<0.01, p<0.001) in the myocardium following MI induction. Conclusion: We conclude that cardioprotective effect of metformin can be time and concentration dependent and AMPK activation by metformin and subsequent suppression of TLRs activity can be considered as a target in protecting the infracted heart and may indicate a link between AMPK and TLRs.