title: Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia.
abstract: OBJECTIVE
  Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue.
  
  
  METHODS
  Dietary induction of hypercholesterolemia was performed over 20 weeks in Yucatan swine with treated animals receiving atorvastatin 3 mg/kg/day. Chronic myocardial ischemia was induced via surgical placement of an ameroid constrictor ring around the proximal circumflex artery at age 20 weeks, followed by tissue harvest at age 27 weeks. Myocardial levels of protein, lipid, and DNA biomarkers of oxidative stress, serum levels of 8-isoprostane, nitric oxide (NO) dependent, and independent coronary microvascular reactivity, as well as isotope-labeled microsphere myocardial perfusion analysis and histologic analysis for endothelial cell density was performed.
  
  
  RESULTS
  Atorvastatin treatment was associated with elevated levels of myocardial protein oxidation and lipid peroxidation. Conversely, serum oxidant stress biomarkers were not elevated. Atorvastatin treatment improved nitric oxide dependent and independent microvascular reactivity, and was associated with decreased perfusion in the ischemic myocardial territory.
  
  
  CONCLUSIONS
  Treatment with atorvastatin was associated with increased levels of myocardial tissue protein and lipid oxidative stress biomarkers and a reduced functional endogenous angiogenic response, but improved coronary microvascular reactivity. Increased oxidative stress in tissues may play a role in the reduced angiogenic response seen with atorvastatin treatment in other studies.
authors.affiliation: Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.forename: Munir
authors.initials: M
authors.lastname: Boodhwani
authors.forename: Basel
authors.initials: B
authors.lastname: Ramlawi
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Mieno
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Xu
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004247:DNA / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011506:Proteins; D011758:Pyrroles; C075750:8-epi-prostaglandin F2alpha; D000244:Adenosine Diphosphate; D004247:DNA; D002784:Cholesterol; D000069059:Atorvastatin; D015237:Dinoprost