Chronic Metformin Associated Cardioprotection Against Infarction: Not Just a Glucose Lowering Phenomenon

• Published in: Cardiovascular drugs and therapy 2013-02, Vol.27 (1), p.5-16
• Main Authors: Whittington, Hannah J., Hall, Andrew R., McLaughlin, Catarina P., Hausenloy, Derek J., Yellon, Derek M., Mocanu, Mihaela M.
• Format: Article
• Language: English
• Subjects: Aging - blood; Aging - metabolism; Aging - pathology; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Cardiology; Cardiology. Vascular system; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cardiovascular system; Diabetes Mellitus, Experimental - drug therapy; Dose-Response Relationship, Drug; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Male; Medical sciences; Medicine; Medicine & Public Health; 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; Original Article; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pharmacology. Drug treatments; Protein Kinases - metabolism; Rats; Rats, Wistar; RNA-Binding Proteins - biosynthesis; Transcription Factors - biosynthesis
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-012-6425-x

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.