title: Atorvastatin regulates apoptosis in chronically ischemic myocardium.
abstract: BACKGROUND
  We previously demonstrated that atorvastatin upregulates proangiogenic proteins and increases arteriolar density in ischemic myocardium. Despite this, there was a lack of collateral-dependent perfusion, possibly related to apoptosis. We utilized a swine model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of atorvastatin on apoptosis.
  
  
  METHODS
  Sixteen Ossabaw miniswine were fed a high-cholesterol diet for 14 weeks then underwent surgical placement of an ameroid constrictor to their circumflex artery inducing chronic ischemia. Eight pigs additionally received supplemental atorvastatin (1.5 mg/kg daily). Myocardium was harvested six months later for western blotting and TUNEL staining.
  
  
  RESULTS
  Animals supplemented with atorvastatin had significant increases in markers associated with apoptosis including p-38, BAX, and caspase 3 (p < 0.05). Atorvastatin supplementation also resulted in significant increases in expression of cell survival proteins Bcl-2 and P-ERK and an overall decrease in apoptosis demonstrated by TUNEL staining (p < 0.05).
  
  
  CONCLUSIONS
  Atorvastatin acts on multiple pathways and its effects on angiogenesis remain unclear. Although there is increased expression in several markers of apoptosis, key anti-apoptotic proteins were also upregulated with an overall decrease in apoptosis. Further investigation of these pathways may provide insight into the role of statins on myocardial protection after ischemia.
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Sabe
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Sadek
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Dalal
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D053148:Caspase 3 / Q000235:genetics / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000235:genetics*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D024821:Metabolic Syndrome / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000166:cytology* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D051028:bcl-2-Associated X Protein; D000069059:Atorvastatin; D053148:Caspase 3