Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells

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

Research output: Contribution to journalArticle

218 Scopus citations

Abstract

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-α 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.

Original languageEnglish (US)
Pages (from-to)1640-1645
Number of pages6
JournalCirculation
Volume108
Issue number13
DOIs
StatePublished - Sep 30 2003

Keywords

  • Pulmonary heart disease
  • Remodeling
  • Statins
  • Vasculature

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells'. Together they form a unique fingerprint.

  • Cite this

    Nishimura, T., Vaszar, L. T., Faul, J. L., Zhao, G., Berry, G. J., Shi, L., Qiu, D., Benson, G., Pearl, R. G., & Kao, P. N. (2003). Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 108(13), 1640-1645. https://doi.org/10.1161/01.CIR.0000087592.47401.37