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Published ahead of print on August 15, 2002, doi:10.1164/rccm.200203-268OC

Am. J. Respir. Crit. Care Med., Volume 166, Number 10, November 2002, 1403-1408

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Submitted on April 1, 2002
Accepted on August 6, 2002

Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats

Toshihiko Nishimura1, John L Faul1, Gerald J Berry2, Laszlo Vaszar1, Daoming Qiu1, Ronald G Pearl3, and Peter N Kao1*

1 Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA, USA, 2 Pathology, Stanford University Medical Center, Stanford, CA, USA, 3 Anesthesiology, Stanford University Medical Center, Stanford, CA, USA

* To whom correspondence should be addressed. E-mail: peterkao{at}stanford.edu.

Hypertensive pulmonary vascular disease (HPVD) involves abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure and death. Compounds with antiproliferative effects on endothelial and smooth muscle cells, such as HMG CoA-reductase inhibitors, may prevent the development of experimental HPVD. Pneumonectomized rats injected with monocrotaline at 7 days develop severe HPVD with neointimal formation. Rats were randomized to receive either vehicle or treatment with the HMG CoA-reductase inhibitor, simvastatin (2 mg/kg/day). By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (mPpa = 53 ± 2 mm Hg) and right ventricular hypertrophy (right ventricle/(left ventricle plus septum)(RV/LV+S = 0.78 ± 0.09) than rats in Groups PMS5-35 (mPpa = 27 ± 3 mm Hg, RV/LV+S = 0.34 ± 0.08; p <= 0.001). Pulmonary vascular remodeling with neointimal formation consisting of smooth muscle cells was more severe in vehicle-treated rats (1.98 ± 0.02), than in Group PMS5-35 (0.59 ± 0.46; p < 0.001). Additionally, lung endothelial nitric oxide synthase (eNOS) expression was decreased in vehicle-treated animals but was restored toward normal by simvastatin. Simvastatin attenuates monocrotaline-induced vascular remodeling with neointimal formation, pulmonary arterial hypertension, and right ventricular hypertrophy in rats.
Key words: Hypertension, pulmonary ; endothelium ; cholesterol ; nitric oxide synthase




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