Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.
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.
Nishimura
Toshihiko
T
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, Calif 94305-5236, USA.
Vaszar
Laszlo T
LT
Faul
John L
JL
Zhao
Guohua
G
Berry
Gerald J
GJ
Shi
Lingfang
L
Qiu
Daoming
D
Benson
Gail
G
Pearl
Ronald G
RG
Kao
Peter N
PN
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin