Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase
Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase
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DOI：
10.1002/ppul.23610
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发表时间：
2017-04-01
影响因子：
3.1
通讯作者：
Dai, Zen-Kong
中科院分区：
文献类型：
--
作者：
Chen, I-Chen;Tan, Mian-Shin;Dai, Zen-Kong
背景：肺动脉高压（PH）是一种毁灭性的疾病，没有任何治疗方法可以治愈。据报道，肺血管重构与平均肺动脉压升高和内皮型一氧化氮合酶（eNOS）、内皮素-1 （ET-1）、RhoA/ rhoh激酶导致PH的发展。氧化应激和RhoA/ rhoh激酶途径也被认为参与PH的病理生理。他汀类药物是具有多效作用的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（HMG-CoA还原酶抑制剂），是治疗PH的潜在药物。在本研究中，我们研究了辛伐他汀对左心室功能障碍继发性PH发展的有益作用。方法建立6周龄主动脉束带大鼠继发性左心室功能障碍模型。观察早期治疗组肺组织Rho激酶、ET-1、eNOS、p-eNOS、亚硝酸盐/硝酸盐（NOx）、cGMP、p47（Phox）、p67（Phox）的表达情况，早期治疗组第1 ~ 42天给予辛伐他汀（30mg/kg/day），晚期治疗组第29 ~ 42天给予辛伐他汀（30mg/kg/day）。结果辛伐他汀降低了早期和晚期治疗组的平均肺动脉压、肺动脉重塑、血浆脑利钠肽、ET-1、活性氧和NADPH氧化酶2调节亚基p47（Phox）和p67(Phox)，并上调了肺p-eNOS、NOx和cGMP。结论抑制HMG-CoA还原酶可能通过rho激酶途径和NADPH氧化酶预防和减轻左心功能障碍患者PH的发展。需要对人类进行转化研究来证实这些发现。儿科肺科杂志，2017;52:43 -457。(c) 2016 Wiley Periodicals, Inc.；
BackgroundPulmonary hypertension (PH) is a devastating disorder, for which no therapy is curative. It has been reported that pulmonary vascular remodeling, associated with increasing mean pulmonary arterial pressure and upregulated expression of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), RhoA/RhoH-kinase results in the development of PH. Oxidative stress and the RhoA/Rho-kinase pathway are also thought to be involved in the pathophysiology of PH. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) with pleiotropic effects and are potential agents for the treatment of PH. In this study, we investigated the beneficial effects of simvastatin on the development of PH secondary to left ventricular dysfunction.MethodsA PH secondary to left ventricular dysfunction model was established in 6-week-old aortic-banded rats. The pulmonary expression of Rho kinase, ET-1, eNOS, p-eNOS, nitrite/nitrate (NOx), cGMP, p47(Phox), and p67(Phox) were investigated in the early-treatment group, to which was administered simvastatin (30mg/kg/day) from days 1 to 42 or the late-treatment group, to which was administered simvastatin (30mg/kg/day) from days 29 to 42.ResultsSimvastatin attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, plasma brain natriuretic peptide, ET-1, reactive oxygen species, and the NADPH oxidase 2 regulatory subunits, p47(Phox) and p67(Phox), and upregulated pulmonary p-eNOS, NOx, and cGMP in both the early- and late-treated groups.ConclusionsInhibiting HMG-CoA reductase may have therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase. A translational study in humans is needed to substantiate these findings. Pediatr Pulmonol. 2017;52:443-457. (c) 2016 Wiley Periodicals, Inc.