High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine
| Autor: | Jian Li, Frank W. Sellke, Munir Boodhwani, Shigetoshi Mieno, Pierre Voisine, Jun Feng, Neel R. Sodha |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Pulmonary and Respiratory Medicine medicine.medical_specialty Swine Angiogenesis Atorvastatin Hypercholesterolemia Basic fibroblast growth factor Neovascularization Physiologic 030204 cardiovascular system & hematology Neovascularization 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Pyrroles Endothelial dysfunction 030304 developmental biology 0303 health sciences business.industry Anticholesteremic Agents medicine.disease Coronary Vessels 3. Good health Vascular endothelial growth factor Vascular endothelial growth factor A Endocrinology chemistry Heptanoic Acids Swine Miniature Female Surgery Endostatin medicine.symptom Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | The Journal of Thoracic and Cardiovascular Surgery. 132:1299-1306 |
| ISSN: | 0022-5223 |
| Popis: | ObjectivesThe 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.MethodsYucatan 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·kg−1·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 μg 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.ResultsHypercholesterolemic 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.ConclusionsAtorvastatin 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. |
| Databáze: | OpenAIRE |
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