Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats.
BACKGROUND
Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway.


METHODS
Simvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 micromol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1.


RESULTS
Simvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 +/- 2.2 mm Hg to 22.1 +/- 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 +/- 0.8 mm Hg to 17.5 +/- 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression.


CONCLUSIONS
This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.
Hsu
Hsao-Hsun
HH
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC. ntuhfred@yahoo.com.tw
Ko
Wen-Je
WJ
Hsu
Jo-Yu
JY
Chen
Jin-Shing
JS
Lee
Yung-Chie
YC
Lai
I-Rue
IR
Chen
Chau-Fong
CF
D000818:Animals; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000008:administration & dosage*; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat