Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

Abstract

OBJECTIVE-Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury.RESEARCH DESIGN AND METHODS-Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 g/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion.RESULTS-Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177.CONCLUSIONS-These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection. Diabetes 57:696-705, 2008 M etformin is one of the most commonly prescribed antihyperglycemic agents for the treatment of type 2 diabetes (1). Its major effects in terms of blood glucose are mediated through a reduction in hepatic glucose output and an increase in insulin-dependent peripheral glucose utilization (2). The therapeutic effects of metformin, however, are not limited to its ability to lower blood glucose, as evidence supports direct vascular effects (3,4). Additionally, two large-scale clinical trials have reported that metformin improves vascular function and reduces mortality and cardiovascular end points of type 2 diabetic subjects (5,6) by actions that cannot be attributed entirely to its antihyperglycemic effects (7).Recent studies suggest that the pleotropic effects of metformin may be mediated by its activation of AMPactivated protein kinase (AMPK) (1,8,9), a protein kinase that is activated in response to alterations in cellular energy levels (10). Its activation is mediated by increases in AMP-to-ATP ratios through mechanisms involving allosteric regulation of AMPK subunits, making it a better substrate for upstream AMPK kinases (AMPKK) and a worse substrate for competing protein phosphatases (11). Metabolic activators of AMPK include ischemia, oxidative stress, exercise, and glucose deprivation (12). When activated, AMPK stimulates fatty acid oxidation (13), promotes glucose transport (14), accelerates glycolysis (15), and inhibits triglyceride (16) and ...

Metformin and heart failure: never say never again

“…In addition, metformin may exert cardioprotective actions, possibly by AMPK activation and reduced cardiac fibrosis [30][31][32][33][34][35]37]. However, we need longer follow-up data and more information as to the role of the severity of HF.…”

“…Three mechanisms have hitherto been proposed. Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35].…”

“…Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35]. Thus, plasma and myocardial levels of nitric oxide increase [30,31], ultimately resulting in improved endothelial function, preservation of left ventricular ejection fraction [30,31,33,35], reduced left ventricular dilatation [30,33,35], improved left ventricular end-diastolic pressure [31,35] and also reduced myocardial autophagy [34] and apoptosis [31].…”

“…Furthermore, although some workers have performed multivariate analyses to exclude potential confounding factors [20][21][22][23][24][25][26], the latter have not always been entirely convincingly accounted for. Fifth, and final, most of the information on the mechanisms of action for metformin are currently derived from experimental research [30][31][32][33][34][35]37,39] and need further clinical study.…”

Expressão do precondicionamento isquêmico em pacientes com diabetes mellitus tipo 2 e doença arterial coronariana

“…Ainda que alguns trabalhos experimentais demonstrem que o diabetes pode alterar algumas vias intracelulares do PI, como as vias da quinase 3 do fosfatidil-inositol (37) ou a função dos canais de potássio dependentes de ATP (38) , prejudicando a expressão do PI, o conjunto destes estudos experimentais tem demonstrado resultados conflitantes (39) . Mesmo que alguns trabalhos demonstrem que o diabetes não interfere substancialmente no PI (40,41) , muitos sugerem influência negativa (42)(43)(44) . (17,18,45) .…”