title: High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine.
abstract: OBJECTIVE
  The disappointing results of myocardial angiogenic therapy have been attributed, in part, to endothelial dysfunction present in patients with coronary disease. Statins have established proendothelial properties but seem to have dose-dependent effects on angiogenesis. We investigated the functional and molecular effects of high-dose atorvastatin on vascular endothelial growth factor-induced myocardial angiogenesis in hypercholesterolemic swine.
  
  
  METHODS
  Yucatan miniswine (20-30 kg) were fed either a normal (ND group, n = 8) or high-cholesterol diet, with (HC-ATOR group, n = 8) or without (HC group, n = 8) atorvastatin (3 mg x kg(-1) x d(-1)), for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery, followed 3 weeks later by perivascular vascular endothelial growth factor administration (2 microg over 4 weeks) with a sustained release osmotic pump. Microvessel relaxation responses, myocardial perfusion, and myocardial expression of angiogenic mediators were assessed 4 weeks later.
  
  
  RESULTS
  Hypercholesterolemic swine demonstrated impaired microvessel relaxation to vascular endothelial growth factor (P < .01 vs ND group) and adenosine diphosphate (P < .001 vs ND group), which was normalized in the HC-ATOR group. After perivascular vascular endothelial growth factor administration, collateral-dependent myocardial perfusion was significantly increased in the ND group but decreased in both the HC and HC-ATOR groups (both P < .01 vs the ND group). The animals in the HC-ATOR group demonstrated increased myocardial expression of the antiangiogenic protein endostatin and increased Akt phosphorylation without significant changes in Akt and endothelial nitric oxide synthase expression.
  
  
  CONCLUSIONS
  Atorvastatin treatment reverses hypercholesterolemia-induced endothelial dysfunction without appreciable improvements in collateral-dependent myocardial perfusion in response to vascular endothelial growth factor treatment. Increased myocardial endostatin expression and chronic Akt activation, associated with atorvastatin therapy, might account for the lack of improvement in the angiogenic response to vascular endothelial growth factor therapy.
authors.affiliation: Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA.
authors.forename: Munir
authors.initials: M
authors.lastname: Boodhwani
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Mieno
authors.forename: Pierre
authors.initials: P
authors.lastname: Voisine
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Neel
authors.initials: N
authors.lastname: Sodha
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D000069059:Atorvastatin; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000503:physiopathology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011758:Pyrroles / Q000008:administration & dosage*; D013552:Swine; D013556:Swine, Miniature; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000069059:Atorvastatin