Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon

Cardiovasc Drugs Ther. 2013 Feb;27(1):5-16. doi: 10.1007/s10557-012-6425-x.

Abstract

Purpose: Clinical and experimental investigations demonstrated that metformin, a widely used anti-diabetic drug, exhibits cardioprotective properties against myocardial infarction. Interestingly, metformin was previously shown to increase the expression of PGC-1α a key controller of energy metabolism in skeletal muscle, which is down-regulated in diabetic conditions. We hypothesized that chronic treatment with metformin could protect the aged, diabetic heart against ischemia-reperfusion injury (IRI) by up-regulating PGC-1α and improving the impaired functionality of diabetic mitochondria.

Methods: Following 4 weeks of metformin (300 mg/kg) administered in the drinking water, 12 month-old diabetic Goto Kakizaki and non-diabetic Wistar rat hearts were assigned for infarct measurement following 35 min ischemia and 60 min reperfusion or for electron microscopy (EM) and Western blotting (WB) investigations.

Results: Metformin elicited a cardioprotective effect in both non-diabetic and diabetic hearts. In contrast with the diabetic non-treated hearts, the diabetic hearts treated with metformin showed more organized and elongated mitochondria and demonstrated a significant increase in phosphorylated AMPK and in PGC-1α expression.

Conclusions: In summary these results show for the first time that chronic metformin treatment augments myocardial resistance to ischemia-reperfusion injury, by an alternative mechanism in addition to the lowering of blood glucose. This consisted of a positive effect on mitochondrial structure possibly via a pathway involving AMPK activation and PGC-1α. Thus, metformin prescribed chronically to patients may lead to a basal state of cardioprotection thereby potentially limiting the occurrence of myocardial damage by cardiovascular events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / blood
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Blood Glucose / metabolism*
  • Blotting, Western
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dose-Response Relationship, Drug
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Metformin / administration & dosage
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Microscopy, Electron
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / ultrastructure
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Myocardium / ultrastructure
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Kinases / metabolism
  • RNA-Binding Proteins / biosynthesis
  • Rats
  • Rats, Wistar
  • Transcription Factors / biosynthesis

Substances

  • Blood Glucose
  • Cardiotonic Agents
  • Hypoglycemic Agents
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • RNA-Binding Proteins
  • Transcription Factors
  • Metformin
  • Protein Kinases
  • AMP-activated protein kinase kinase