Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats.
Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats.
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DOI：
10.1186/1465-9921-10-32
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发表时间：
2009-05-02
影响因子：
5.8
通讯作者：
Chen CF
中科院分区：
文献类型：
--
作者：
Hsu HH;Ko WJ;Hsu JY;Chen JS;Lee YC;Lai IR;Chen CF
在实验动物模型中，辛伐他汀已显示通过多种机制改善肺动脉高压。在这项研究中，我们假设辛伐他汀对肺动脉高压的主要益处是通过血红素加氧酶-1途径实现的。辛伐他汀（10毫克/公斤/天）进行了测试，在两个大鼠模型的肺动脉高压（PH）：野百合碱管理和慢性缺氧。在两种模型中，用和不用辛伐他汀治疗，测定血流动力学变化、右心肥大、肺HO-1蛋白表达和血红素氧合酶（HO）活性。使用HO活性的强效抑制剂锡-原卟啉（SnPP，20 μmol/kg w/d）来确认HO-1的作用。辛伐他汀显著改善肺动脉高压，在野百合碱诱导的PH（MCT-PH）大鼠中从38.0 ± 2.2 mm Hg降至22.1 ± 1.9 mm Hg，在慢性缺氧诱导的PH（CH-PH）大鼠中从33.3 ± 0.8 mm Hg降至17.5 ± 2.9 mm Hg。辛伐他汀可显著降低MCT-PH和CH-PH大鼠右心室肥厚的严重程度。与SnPP联合给药消除了辛伐他汀的益处。辛伐他汀显著增加PH大鼠肺组织HO-1蛋白表达和HO活性;而同时给予SnPP仅降低HO-1活性。这些观察结果表明，辛伐他汀诱导的肺动脉高压的改善与HO-1的活性直接相关，而不是其表达。这项研究表明，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。
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 μmol/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.
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影响因子：
4.8
作者：
Lee, PJ;Jiang, BH;Choi, AMK
通讯作者：
Choi, AMK
DOI：
10.1152/ajpheart.1996.270.1.h107
发表时间：
1996-01-01
影响因子：
4.8
作者：
Motterlini, R;Foresti, R;Winslow, RM
通讯作者：
Winslow, RM
影响因子：
168.9
作者：
Massy, ZA;Keane, WF;Kasiske, BL
通讯作者：
Kasiske, BL
DOI：
10.1073/pnas.161272598
发表时间：
2001-07-17
影响因子：
11.1
作者：
Minamino, T;Christou, H;Kourembanas, S
通讯作者：
Kourembanas, S
DOI：
10.1152/ajpheart.01097.2002
发表时间：
2003-09-01
影响因子：
4.8
作者：
Girgis, RE;Li, DC;Johns, RA
通讯作者：
Johns, RA