High-dose atorvastatin improves hypercholesterolemic coronary endothelial dysfunction without improving the angiogenic response

Circulation. 2006 Jul 4;114(1 Suppl):I402-8. doi: 10.1161/CIRCULATIONAHA.105.000356.

Abstract

Background: Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine.

Methods and results: Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29+/-3% versus 61+/-6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67+/-2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (-0.27+/-0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (-0.35+/-0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (-68+/-8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210+/-48%; P=0.004 versus NORM).

Conclusions: Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Adenosine Diphosphate / pharmacology
  • Angiostatins / biosynthesis
  • Angiostatins / genetics
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis Inducing Factor / biosynthesis
  • Apoptosis Inducing Factor / genetics
  • Arterioles / drug effects
  • Arterioles / physiopathology
  • Atorvastatin
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / genetics
  • Cholesterol / blood
  • Coronary Circulation
  • Coronary Vessels / pathology*
  • Drug Evaluation, Preclinical
  • Endostatins / biosynthesis
  • Endostatins / genetics
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / pathology
  • Female
  • Fibroblast Growth Factor 2 / biosynthesis
  • Fibroblast Growth Factor 2 / genetics
  • Gene Expression Regulation / drug effects*
  • Heptanoic Acids / therapeutic use*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / pathology
  • Male
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Myocardial Ischemia / etiology*
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / physiopathology
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / genetics
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type III / biosynthesis
  • Nitric Oxide Synthase Type III / genetics
  • Nitroprusside / pharmacology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Pyrroles / therapeutic use*
  • Receptor, TIE-2 / biosynthesis
  • Receptor, TIE-2 / genetics
  • Swine
  • Swine, Miniature
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vasodilation / drug effects

Substances

  • Apoptosis Inducing Factor
  • Endostatins
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Nitroprusside
  • Nitric Oxide
  • Adenosine Diphosphate
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Angiostatins
  • Cholesterol
  • Atorvastatin
  • Nitric Oxide Synthase Type III
  • Receptor, TIE-2
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Caspases
  • Matrix Metalloproteinase 9