Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats
Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats
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DOI：
10.1097/00004872-200501000-00017
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发表时间：
2005-01-01
影响因子：
4.9
通讯作者：
Matsuoka, H
中科院分区：
文献类型：
--
作者：
Mita, S;Kobayashi, N;Matsuoka, H
目的Rho激酶在多种细胞功能中起着重要作用。为了阐明Rho激酶介导的体内心血管重塑的分子机制，我们评估了是否涉及通过Rho的信号通路，以及是否Y-27632，一种特异性Rho激酶抑制剂，刺激内皮型一氧化氮合酶（eNOS），抑制氧化应激和凝集素样氧化低密度脂蛋白受体-1（LOX-1）途径在达尔盐敏感性高血压左心室（方法给予Y-27632（每天3 mg/kg）或载体5周，从6周龄至左心室肥大阶段（111周）。结果Y-27632能显著改善肥厚期大鼠左心室重量的增加。Y-27632可抑制肥大期RhoA蛋白、Rho激酶基因表达和肌球蛋白轻链磷酸化。Y-27632可抑制DS大鼠NAD（P）H氧化酶p22 phox、p47 phox、gp 91 phox和LOX-1表达的增加。Y-27632降低了DS大鼠中上调的蛋白激酶C β和p65核因子-κ B磷酸化。相反，Y-27632可上调肥厚期eNOS表达下调，有效抑制血管病变形成，如中膜厚度和血管周围纤维化，抑制转化生长因子β 1、I型和III型胶原，和纤维连接蛋白基因表达。结论抑制Rho-激酶通路可能在与eNOS和氧化应激-LOX-1通路相关的DS大鼠心血管重构的心脏保护作用中起关键作用，至少可能是高血压伴心肌肥厚的潜在治疗策略。(C)2005年利平科特威廉姆斯威尔金斯。
Objectives Rho-kinase plays a crucial role in various cellular functions. To elucidate molecular mechanisms of Rho-kinase-mediated cardiovascular remodeling in vivo, we evaluated whether a signaling pathway through Rho is involved, and whether Y-27632, a specific Rho-kinase inhibitor, stimulates endothelial nitric oxide synthase (eNOS) and suppresses the oxidative stress and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway in the left ventricle of Dahl salt-sensitive hypertensive (DS) rats.Methods Y-27632 (3 mg/kg per day) or vehicle were given for 5 weeks, from age 6 weeks to a stage of left ventricular hypertrophy (111 weeks). Age-matched Dahl salt-resistant (DR) rats fed the same diet served as a control group.Results Increased left ventricular weight in the hypertrophy stage was significantly ameliorated by Y-27632. Upregulated RhoA protein, Rho-kinase gene expression and myosin light-chain phosphorylation in the hypertrophy stage were suppressed by Y-27632. Increased expression of NAD(P)H oxidase p22phox, p47phox, gp91 phox and LOX-1 in DS rats were inhibited by Y-27632. Upregulated protein kinase Cepsilon and p65 nuclear factor-kappaB phosphorylation in DS rats was reduced by Y-27632. In contrast, downregulated eNOS expression in hypertrophy stage was upregulated by Y-27632, Y-27632 effectively inhibited vascular lesion formation, such as medial thickness and perivascular fibrosis, and suppressed transforming growth factor-beta1, type I and III collagen, and fibronectin gene expression.Conclusions Inhibiting the Rho-kinase pathway may play a key role in the cardioprotective effect on cardiovascular remodeling associated with eNOS and the oxidative stress-LOX-1 pathway in DS rats, and may be at least a potential therapeutic strategy for hypertension with cardiac hypertrophy. (C) 2005 Lippincott Williams Wilkins.