Hsu Hsao-Hsun, Ko Wen-Je, Hsu Jo-Yu, Chen Jin-Shing, Lee Yung-Chie, Lai I-Rue, Chen Chau-Fong
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Respir Res. 2009 May 2;10(1):32. doi: 10.1186/1465-9921-10-32.
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.
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.
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.
This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.
在实验动物模型中，辛伐他汀已被证明可通过多种机制改善肺动脉高压。在本研究中，我们假设辛伐他汀在肺动脉高压中的主要益处是通过血红素加氧酶-1途径实现的。
在两种肺动脉高压（PH）大鼠模型中测试辛伐他汀（10mg/kg体重/天）：给予野百合碱和慢性缺氧。在有或没有辛伐他汀治疗的两种模型中，测量血流动力学变化、右心室肥厚、HO-1蛋白表达和肺中的血红素加氧酶（HO）活性。锡原卟啉（SnPP，20μmol/kg体重/天），一种有效的HO活性抑制剂，用于证实HO-1的作用。
在野百合碱诱导的肺动脉高压（MCT-PH）中，辛伐他汀使肺动脉高压从38.0±2.2mmHg显著改善至22.1±1.9mmHg，在慢性缺氧诱导的肺动脉高压（CH-PH）大鼠中从33.3±0.8mmHg改善至17.5±2.9mmHg。在MCT-PH和CH-PH大鼠中，辛伐他汀显著降低了右心室肥厚的严重程度。与SnPP共同给药消除了辛伐他汀的益处。辛伐他汀显著增加了PH大鼠肺中的HO-1蛋白表达和HO活性；然而，与SnPP共同给药仅降低了HO-1活性。这些观察结果表明，辛伐他汀诱导的肺动脉高压改善与HO-1的活性直接相关，而不是其表达。
本研究表明，辛伐他汀治疗主要通过HO-1依赖性途径改善已建立的肺动脉高压。
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