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Diabetes. 2008 Mar;57(3):696-705. Epub 2007 Dec 14.

Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling.

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1
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.

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 microg/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.

PMID:
18083782
DOI:
10.2337/db07-1098
[Indexed for MEDLINE]
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