title: Atorvastatin increases oxidative stress and modulates angiogenesis in Ossabaw swine with the metabolic syndrome.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate the effect of atorvastatin on oxidative stress and angiogenesis in ischemic myocardium in a clinically relevant porcine model of the metabolic syndrome.
  
  
  METHODS
  Sixteen Ossabaw pigs were fed either a high-fat diet alone or a high-fat diet supplemented with atorvastatin (1.5 mg/kg daily) for 14 weeks. Chronic myocardial ischemia was induced by ameroid constrictor placement around the circumflex artery. After 6 months of the diet, myocardial perfusion was measured at rest and with demand pacing. The heart was harvested for analysis of perfusion, microvessel relaxation, protein expression, and oxidative stress.
  
  
  RESULTS
  Both groups had similar endothelium-dependent microvessel relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside. Myocardial perfusion in the ischemic territory was also not significantly different either at rest or with demand pacing. Atorvastatin treatment increased total myocardial protein oxidation and serum lipid peroxidation. However, the expression of markers of oxidative stress, including NOX2, RAC1, myeloperoxidase, and superoxide dismutase 1, 2, and 3, were not statistically different. The expression of proangiogenic proteins endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase (Ser 1177), phosphorylated adenosine monophosphate kinase (Thr 172), phosphorylated extracellular signal-regulated kinase (T202, Y204), and vascular endothelial growth factor were all upregulated in the atorvastatin group.
  
  
  CONCLUSIONS
  Atorvastatin increased the capillary and arteriolar density and upregulated the proangiogenic proteins endothelial nitric oxide synthase and phosphorylated endothelial nitric oxide synthase, phosphorylated adenosine monophosphate kinase, phosphorylated extracellular signal-regulated kinase, and vascular endothelial growth factor in a swine model of the metabolic syndrome. However, it failed to increase myocardial perfusion. Atorvastatin treatment was associated with increased myocardial and serum oxidative stress, which might contribute to the lack of collateral-dependent perfusion in the setting of angiogenesis.
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI 02905, USA.
authors.forename: Nassrene Y
authors.initials: NY
authors.lastname: Elmadhun
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Lassaletta
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D003097:Collateral Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D055414:Myocardial Perfusion Imaging; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins; D015415:Biomarkers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014665:Vasodilator Agents; D000069059:Atorvastatin