Abstract

Objective: Clinical studies have reported that metformin reduces cardiovascular end points of type-2 diabetics 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 anti-hyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury.

Research Design and Methods: Non-diabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 μg/kg) or vehicle (saline) was administered either prior to ischemia or at the time of reperfusion.

Results: Administration of metformin prior to ischemia or at reperfusion decreased myocardial injury in both non-diabetic 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.