High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response
Autor: | Jian Li, Frank W. Sellke, Munir Boodhwani, Roger J. Laham, Yasunari Nakai, Cesario Bianchi, Pierre Voisine, Jun Feng, Shigetoshi Mieno, Basel Ramlawi |
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Rok vydání: | 2006 |
Předmět: |
Male
Vascular Endothelial Growth Factor A Swine Angiogenesis Atorvastatin Drug Evaluation Preclinical Myocardial Ischemia Apoptosis chemistry.chemical_compound Phosphorylation Endothelial dysfunction biology Caspase 3 Apoptosis Inducing Factor Coronary Vessels Receptor TIE-2 Endostatins Adenosine Diphosphate Vasodilation Vascular endothelial growth factor Arterioles Cholesterol medicine.anatomical_structure Matrix Metalloproteinase 9 Proto-Oncogene Proteins c-bcl-2 Caspases HMG-CoA reductase Swine Miniature Female Fibroblast Growth Factor 2 lipids (amino acids peptides and proteins) Endostatin Cardiology and Cardiovascular Medicine Perfusion medicine.drug Nitroprusside medicine.medical_specialty Nitric Oxide Synthase Type III Endothelium Hypercholesterolemia Neovascularization Physiologic Nitric Oxide Coronary Circulation Physiology (medical) Internal medicine medicine Animals Pyrroles Angiostatins business.industry medicine.disease Endocrinology Gene Expression Regulation chemistry Heptanoic Acids 15-Hydroxy-11 alpha 9 alpha-(epoxymethano)prosta-5 13-dienoic Acid biology.protein Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors business Protein Processing Post-Translational Proto-Oncogene Proteins c-akt |
Zdroj: | Circulation. 114 |
ISSN: | 1524-4539 0009-7322 |
DOI: | 10.1161/circulationaha.105.000356 |
Popis: | 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 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 P P =0.001), decreased vascular endothelial growth factor expression (−68±8%; P 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. |
Databáze: | OpenAIRE |
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