title: Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemia: role of endostatin and oxidative stress.
abstract: BACKGROUND
  Recent studies have shown that angiogenesis is regulated by a balance between activators and inhibitors. We investigated the effects of hypercholesterolemia on the functional angiogenic response and collateral formation induced by chronic myocardial ischemia and the expression of angiogenic mediators.
  
  
  METHODS
  Twelve Yucatan miniswine, fed either a normal (NORM, n = 6) or high cholesterol (HCHO, n = 6) diet for 13 weeks, underwent ameroid constrictor placement around the circumflex artery. Three weeks later, myocardial perfusion was quantified using isotope-labeled microspheres. Seven weeks after ameroid placement, coronary microvascular responses and myocardial perfusion were assessed. Vascular density was evaluated by PECAM-1 (CD-31) staining, and vascular endothelial growth factor, endothelial nitric oxide synthase, endostatin, and angiostatin protein levels were determined. Myocardial protein oxidation was quantified.
  
  
  RESULTS
  Coronary microvessels from HCHO pigs showed significant endothelial dysfunction. Baseline-adjusted myocardial flow at 7 weeks was significantly reduced in the HCHO animals (-0.002 +/- 0.06 versus +0.23 +/- 0.09 mL/min/g, HCHO versus NORM, p = 0.04). Endostatin expression was significantly increased in the HCHO pigs (2.2-fold, p = 0.001 versus NORM). There was a mild reduction in myocardial vascular endothelial growth factor expression (-29% +/- 14%, p = 0.09) in HCHO animals, but no difference in expression of endothelial nitric oxide synthase and angiostatin. The HCHO animals demonstrated increased myocardial protein oxidation compared with the NORM group (+155% +/- 21%, p = 0.03 versus NORM).
  
  
  CONCLUSIONS
  Ischemia-induced angiogenesis is inhibited in hypercholesterolemic pigs with a concomitant increase in endostatin expression and oxidative stress. These findings suggest that under conditions of hypercholesterolemia, coronary collateral development may be regulated by endogenous angiogenesis inhibitors such as endostatin as well as reactive oxygen species.
authors.affiliation: Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Munir
authors.initials: M
authors.lastname: Boodhwani
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakai
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Mieno
authors.forename: Pierre
authors.initials: P
authors.lastname: Voisine
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Eugenio G
authors.initials: EG
authors.lastname: Araujo
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Keith
authors.initials: K
authors.lastname: Michael
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D043169:Endostatins / Q000096:biosynthesis / Q000502:physiology*; D006937:Hypercholesterolemia / Q000150:complications*; D007150:Immunohistochemistry; D017202:Myocardial Ischemia / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism; D013552:Swine
chemical_list: D043169:Endostatins; D011506:Proteins