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

Munir Boodhwani; Yasunari Nakai; Pierre Voisine; Jun Feng; Jian Li; Shigetoshi Mieno; Basel Ramlawi; Cesario Bianchi; Roger Laham; Frank W Sellke

doi:10.1161/circulationaha.105.000356

PubMed · 16820608

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

Munir Boodhwani·Yasunari Nakai·Pierre Voisine·Jun Feng·Jian Li·Shigetoshi Mieno·Basel Ramlawi·Cesario Bianchi·Roger Laham·Frank W Sellke

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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.

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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid Adenosine Diphosphate Angiostatins Animals Apoptosis Apoptosis Inducing Factor Arterioles Atorvastatin Caspase 3 Caspases Cholesterol Coronary Circulation Coronary Vessels Drug Evaluation, Preclinical Endostatins Endothelium, Vascular Female Fibroblast Growth Factor 2 Gene Expression Regulation Heptanoic Acids Hydroxymethylglutaryl-CoA Reductase Inhibitors Hypercholesterolemia Male Matrix Metalloproteinase 9 Myocardial Ischemia Neovascularization, Physiologic Nitric Oxide Nitric Oxide Synthase Type III Nitroprusside Phosphorylation Protein Processing, Post-Translational Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 Pyrroles Receptor, TIE-2 Swine Swine, Miniature Vascular Endothelial Growth Factor A Vasodilation Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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Munir Boodhwani, Yasunari Nakai, Pierre Voisine, Jun Feng, Jian Li, Shigetoshi Mieno, Basel Ramlawi, Cesario Bianchi, Roger Laham, Frank W Sellke. 2006-07-04. High-dose atorvastatin improves hypercholesterolemic coronary endothelial dysfunction without improving the angiogenic response.. https://doi.org/10.1161/circulationaha.105.000356

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