title: Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.
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.
  
  
  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 x kg(-1) x 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-alpha 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, Calif 94305-5236, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Laszlo T
authors.initials: LT
authors.lastname: Vaszar
authors.forename: John L
authors.initials: JL
authors.lastname: Faul
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Berry
authors.forename: Lingfang
authors.initials: L
authors.lastname: Shi
authors.forename: Daoming
authors.initials: D
authors.lastname: Qiu
authors.forename: Gail
authors.initials: G
authors.lastname: Benson
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Pearl
authors.forename: Peter N
authors.initials: PN
authors.lastname: Kao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D020869:Gene Expression Profiling; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D008168:Lung / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D019821:Simvastatin / Q000627:therapeutic use*; D016019:Survival Analysis; D017539:Tunica Intima / Q000473:pathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin