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

Toshihiko Nishimura, Laszlo 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

215 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Simvastatin
Pulmonary Hypertension
Smooth Muscle Myocytes
Apoptosis
Pulmonary Artery
Monocrotaline
Pressure
Bone Morphogenetic Protein Receptors
jun Genes
Right Ventricular Hypertrophy
fos Genes
Neointima
Nitric Oxide Synthase Type III
Poisons
Vascular System Injuries
Lung Injury
Alkaloids
Smooth Muscle
Blood Vessels
Cell Cycle

Keywords

  • Pulmonary heart disease
  • Remodeling
  • Statins
  • Vasculature

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. / Nishimura, Toshihiko; Vaszar, Laszlo; Faul, John L.; Zhao, Guohua; Berry, Gerald J.; Shi, Lingfang; Qiu, Daoming; Benson, Gail; Pearl, Ronald G.; Kao, Peter N.

In: Circulation, Vol. 108, No. 13, 30.09.2003, p. 1640-1645.

Research output: Contribution to journalArticle

Nishimura, T, Vaszar, L, Faul, JL, Zhao, G, Berry, GJ, Shi, L, Qiu, D, Benson, G, Pearl, RG & Kao, PN 2003, 'Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells', Circulation, vol. 108, no. 13, pp. 1640-1645. https://doi.org/10.1161/01.CIR.0000087592.47401.37
Nishimura, Toshihiko ; Vaszar, Laszlo ; Faul, John L. ; Zhao, Guohua ; Berry, Gerald J. ; Shi, Lingfang ; Qiu, Daoming ; Benson, Gail ; Pearl, Ronald G. ; Kao, Peter N. / Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. In: Circulation. 2003 ; Vol. 108, No. 13. pp. 1640-1645.
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AU - Nishimura, Toshihiko

AU - Vaszar, Laszlo

AU - Faul, John L.

AU - Zhao, Guohua

AU - Berry, Gerald J.

AU - Shi, Lingfang

AU - Qiu, Daoming

AU - Benson, Gail

AU - Pearl, Ronald G.

AU - Kao, Peter N.

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N2 - 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.

AB - 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.

KW - Pulmonary heart disease

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