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

Diabetes. 2008 Mar;57(3):696-705. doi: 10.2337/db07-1098. Epub 2007 Dec 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adenylate Kinase / metabolism*
  • Animals
  • Blood Glucose / drug effects
  • Diabetes Mellitus / metabolism*
  • Gene Deletion
  • Gene Expression Regulation
  • Hypoglycemic Agents / pharmacology
  • Male
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Multienzyme Complexes / metabolism*
  • Myocardial Infarction / prevention & control*
  • Myocardium / pathology
  • Nitric Oxide Synthase Type III / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Reperfusion Injury / complications
  • Signal Transduction / drug effects*


  • Blood Glucose
  • Hypoglycemic Agents
  • Multienzyme Complexes
  • Metformin
  • Nitric Oxide Synthase Type III
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Adenylate Kinase