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


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.
Calvert
John W
JW
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Gundewar
Susheel
S
Jha
Saurabh
S
Greer
James J M
JJ
Bestermann
William H
WH
Tian
Rong
R
Lefer
David J
DJ
D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003920:Diabetes Mellitus / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D009203:Myocardial Infarction / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction / Q000187:drug effects*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase