Published Online
on September 8, 2003

A more recent version of this article appeared on September 30, 2003

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Submitted on January 16, 2003
Revised on May 20, 2003
Accepted on May 21, 2003

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

Toshihiko Nishimura MD, PhD, Laszlo T. Vaszar MD, John L. Faul , Guohua Zhao MD, PhD, Gerald J. Berry MD, Lingfang Shi MD, Daoming Qiu MD, Gail Benson BS, Ronald G. Pearl MD, PhD, and Peter N. Kao MD, PhD^*

From the Division of Pulmonary and Critical Care Medicine (T.N., L.T.V., J.L.F., G.Z., L.S., D.Q., P.N.K.) and the Departments of Pathology (G.J.B.) and Anesthesiology (G.B., R.G.P.), Stanford University Medical Center, Stanford, Calif.

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

Background--Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension.

Methods and Results--Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg^-1 · d^-1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor- and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a.

Conclusions--Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Key words: statins • pulmonary heart disease • vasculature • remodeling

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