Metformin Improves Cardiac Metabolism and Function, and Prevents Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats

Abstract

Background In spontaneously hypertensive rats ( SHR ) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. In this study, we evaluated whether metformin improved myocardial metabolic abnormalities and simultaneously prevented contractile dysfunction and left ventricular hypertrophy in SHR . Methods and Results SHR and control Wistar–Kyoto rats were treated with metformin from 2 to 5 months of age, when SHR hearts exhibit metabolic abnormalities and develop cardiac dysfunction and left ventricular hypertrophy. We evaluated the effect of metformin on myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography. We used cardiac MRI in vivo to assess the effect of metformin on ejection fraction, left ventricular mass, and end‐diastolic wall thickness, and also analyzed metabolites, AMP ‐activated protein kinase and mammalian target‐of‐rapamycin activities, and mean arterial blood pressure. Metformin‐treated SHR had lower mean arterial blood pressure but remained hypertensive. Cardiac glucose uptake rates, left ventricular mass/tibia length, wall thickness, and circulating free fatty acid levels decreased to normal, and ejection fraction improved in treated SHR . Hearts of treated SHR exhibited increased AMP ‐activated protein kinase phosphorylation and reduced mammalian target‐of‐rapamycin activity. Cardiac metabolite profiling demonstrated that metformin decreased fatty acyl carnitines and markers of oxidative stress in SHR . Conclusions Metformin reduced blood pressure, normalized myocardial glucose uptake, prevented left ventricular hypertrophy, and improved cardiac function in SHR . Metformin may exert its effects by normalizing myocardial AMPK and mammalian target‐of‐rapamycin activities, improving fatty acid oxidation, and reducing oxidative stress. Thus, metformin may be a new treatment to prevent or ameliorate chronic hypertension–induced left ventricular hypertrophy.

Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

“…While it remains to be determined as to how these early metabolic changes give rise to LVH, the activation of mTOR has been proposed as a contributing factor. Similarly, profound myocardial metabolic changes have been found to occur prior to the progression of LVH and cardiac dysfunction in spontaneously hypertensive rats [38].…”

ATPase inhibitory factor 1 protects the heart from acute myocardial ischemia/reperfusion injury through activating AMPK signaling pathway

“…There are many literatures that activation of pro-survival kinases, such as ERK and AMPK, can achieve strong cardiac protection in myocardial reperfusion 4,20,31 . Activation of myocardial AMPK has been shown to display salutary effects on ischemic heart disease and glucose homeostasis [32][33][34][35][36] , we, therefore, hypothesized that the AMPK signaling pathway is primarily involved in the protective effects of IF1 as an underlying mechanism. At the cellular level, AMPK activation was found to result from ROS production induced by IF1 treatment.…”

Metformin attenuates angiotensin II‑induced cardiomyocyte hypertrophy by upregulating the MuRF1 and MAFbx pathway

“…The results revealed that metformin significantly suppressed the development of Ang II-induced cardiomyocyte hypertrophy as evidenced by reductions in cardiomyocyte surface area, reduced expression of hypertrophy-associated genes ANP and BNP in Ang II-stimulated cardiomyocytes. Metformin has also been demonstrated to serve cardioprotective effects by reducing left ventricular hypertrophy in patients with coronary artery disease, insulin resistance and pre-diabetes (27,28) Additionally, previous studies have demonstrated that metformin can inhibit protein synthesis by activating MAPK, functioning in the anti-hypertrophic pathway in cardiomyocytes (29,30).…”