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Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats

Division of Pulmonary and Critical Care Medicine, and Departments of Pathology and Anesthesiology, Stanford University Medical Center, Stanford, California

Correspondence and requests for reprints should be addressed to Peter N. Kao, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA 94305-5236. E-mail: peterkao{at}stanford.edu

Hypertensive pulmonary vascular disease is characterized by abnormal proliferation of vascular endothelial and smooth muscle cells, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure, and death. Compounds with antiproliferative effects on vascular endothelial and smooth muscle cells, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may prevent the development of experimental hypertensive pulmonary vascular disease. Pneumonectomized rats injected with monocrotaline at 7 days develop severe hypertensive pulmonary vascular disease with neointimal formation. Rats were randomized to receive either vehicle or treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (53 ± 2 mm Hg) and right ventricular hypertrophy (right ventricle/[left ventricle plus septum] [RV/LV+S] = 0.78 ± 0.09) than rats in Group PMS_5–35 that received simvastatin from Day 5 to 35 (mean pulmonary arterial pressure = 27 ± 3 mm Hg, RV/LV+S = 0.34 ± 0.08; p 0.001). Pulmonary vascular remodeling with neointimal formation consisting of vascular smooth muscle cells was more severe in vehicle-treated rats (vascular occlusion score, 1.98 ± 0.02) than in Group PMS_5–35 (vascular occlusion score, 0.59 ± 0.46; p < 0.001). In addition, lung endothelial nitric oxide synthase gene expression was decreased in vehicle-treated animals but was restored toward normal levels in simvastatin-treated animals. Simvastatin attenuates monocrotaline-induced pulmonary vascular remodeling with neointimal formation, pulmonary arterial hypertension, and right ventricular hypertrophy in rats.

Key Words: cholesterol • endothelium • hypertension, pulmonary • nitric oxide synthase

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