title: Metformin mitigates apoptosis in ischemic myocardium.
abstract: BACKGROUND
  Epidemiologic data has shown that metformin confers a survival advantage in patients with cardiovascular disease. Although the underlying cardioprotective mechanism is unclear, it appears to be independent of metformin's insulin-sensitizing effect. The purpose of this study was to evaluate the effect of metformin on the apoptosis pathway in the ischemic and nonischemic cardiac tissue in a swine model of metabolic syndrome.
  
  
  METHODS
  Ossabaw miniswine were fed either a regular diet (Ossabaw control, n = 8), a high-cholesterol diet (Ossabaw high cholesterol, n = 8), or a high-cholesterol diet supplemented with metformin (Ossabaw high-cholesterol metformin, n = 8). After 9 wk, all animals underwent placement of an ameroid constrictor to the left circumflex coronary artery to induce chronic ischemia. Seven weeks after ameroid placement, animals underwent cardiac harvest.
  
  
  RESULTS
  In the chronically ischemic myocardium, metformin significantly upregulates prosurvival proteins: extracellular signal-regulated kinases, nuclear factor κB, phosphorylated endothelial nitric oxide synthase, and P38. Metformin also significantly inhibits or downregulates proapoptosis proteins: FOXO3 and caspase 3. Metformin decreased the percent apoptotic cells in the ischemic and nonischemic myocardium. There was no difference in arteriolar density, capillary density, intramyocardial fibrosis, or collagen deposition in the ischemic or nonischemic myocardium.
  
  
  CONCLUSIONS
  Metformin selectively alters the apoptosis pathway by inhibiting FOXO3 and decreasing the active form of caspase 3, cleaved caspase 3. Metformin also upregulates mitogen-activated kinase proteins p38 and extracellular signal-regulated protein kinases 1 and 2, which are considered cardioprotective during ischemic preconditioning. Perhaps, the altered activation of the apoptosis pathway in ischemic myocardium is one mechanism by which metformin is cardioprotective.
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors: Nassrene Y
authors: NY
authors: Elmadhun
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors: Ashraf A
authors: AA
authors: Sabe
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors: Antonio D
authors: AD
authors: Lassaletta
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors: Louis M
authors: LM
authors: Chu
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island. Electronic address: fsellke@lifespan.org.
authors: Frank W
authors: FW
authors: Sellke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002316:Cardiotonic Agents; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Apoptosis; Cardioprotection; Metabolic syndrome; Metformin; Myocardial ischemia