Metformin Increases Cardiac Rupture After Myocardial Infarction via the AMPK-MTOR/PGC-1α Signaling Pathway in Rats with Acute Myocardial Infarction

Abstract

BackgroundCardiac rupture often occurs after acute myocardial infarction due to complex and unclear pathogenesis. This study investigated whether metformin increases the incidence of cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.Material/MethodsAn acute myocardial infarction (MI) mouse model was established. A series of experiments involving RT-qPCR, Western blot, TUNEL staining, and Masson staining were performed in this study.ResultsMyocardial infarction occurred, resulting in the cardiac rupture, and the expression level of PGC-1α increased in the cardiac myocardium. Meanwhile, the proportion of myocardial NT-PGC-1α/PGC-1α decreased. The expression level of myocardial PGC-1α in MI mice with cardiac rupture after MI was significantly higher than that in the mice without cardiac rupture, and the ratio of myocardial NT-PGC-1α/PGC-1α was low. In addition, increasing the dose of metformin significantly increased the incidence of cardiac rupture after myocardial infarction in MI mice. High-dose metformin caused cardiac rupture in MI mice. Moreover, high-dose metformin (Met 2.0 nM) reduces the proportion of NT-PGC-1α/PGC-1α in primary cardiomyocytes of SD mice (SD-NRVCs [Neonatal rat ventricular cardiomyocytes]), and its effect was inhibited by Compound C (AMPK inhibitor). Further, after 3 days of treatment with high-dose metformin in MI mice, myocardial fibrin synthesis decreased and fibrosis was significantly inhibited. Meanwhile, cardiomyocyte apoptosis increased significantly. With the increase in metformin concentration, the expression level of myocardial LC3b gradually increased in MI mice, suggesting that metformin enhances the autophagy of cardiomyocytes.ConclusionsThese results suggest that metformin increases cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.

Metformin use and cardiovascular outcomes after acute myocardial infarction in patients with type 2 diabetes: a cohort study

“…In critically ill patients there is a risk of hypoglycaemia-related morbidity associated with intensive glucose control with intravenous insulin [41, 42], although we did not have data on acute glucose control in our study. In pre-clinical studies, increased myocardial rupture after AMI has been observed with metformin, which has been attributed to increased AMPK-MTOR/PGC-1α-mediated cardiomyocyte autophagy, but we were unable to assess this [43].…”

Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo

“…Metformin has been demonstrated to activate the phosphorylation of AMPK in cardiomyocytes and mouse cardiac tissues. In fact, a recent study suggested that short-term treatment with metformin protects against myocardial ischemia-reperfusion injury via the AMPK signaling pathway after myocardial infarction in mice (Hua et al, 2018). Therefore, AMPK has been considered to have various cardioprotective effects in animals and humans.…”

“…Adenosine 5’-monophosphate-activated protein kinase (AMPK) is an essential metabolic regulator for energy sensing and has been well documented (Toyama et al, 2016); AMPK is expressed specifically in various tissues and cells, including cardiomyocytes (Hua et al, 2018), and plays a crucial role in regulating energy metabolism and energy homeostasis under stress conditions. AMPK can be activated by various conditions.…”

“…Previous studies have demonstrated that metformin can protect the heart by inhibiting apoptosis, autophagy, inflammation and other pathways via AMPK (Yuan et al, 2017; Hua et al, 2018; Forslund et al, 2017). However, whether metformin protects against insulin resistance induced by HUA in cardiomyocytes remains unknown.…”

Construction and analysis for differentially expressed long non-coding RNAs and mRNAs in acute myocardial infarction

“…4A,B). KEGG pathway analysis showed that the differentially expressed mRNAs were mostly enriched in viral myocarditis, the mTOR signalling pathway 24 , circadian rhythm, arrhythmogenic right ventricular cardiomyopathy (ARVC), and the metabolism pathway 25 (Fig. 4C,D).…”