title: Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon.
abstract: OBJECTIVE
  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.
authors.affiliation: The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, UCL, London, UK.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Whittington
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.forename: Catarina P
authors.initials: CP
authors.lastname: McLaughlin
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000375:Aging / Q000097:blood / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D008687:Metformin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases