Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration
Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration
复制标题
DOI：
10.1152/ajpheart.00289.2015
复制
发表时间：
2015-12-01
影响因子：
4.8
通讯作者：
Zhu, Yi
中科院分区：
文献类型：
--
作者：
Wang, Qingjie;Huo, Leijun;Zhu, Yi
环氧二十碳三烯酸（EET）对心血管疾病具有有益作用。可溶性环氧化物水解酶 (sEH) 将 EET 代谢为活性较低的二醇，从而降低其生物活性。 sEH 抑制剂可以抑制动物模型中动脉粥样硬化病变的进展。然而，sEH 在血管平滑肌细胞 (VSMC) 中的调节以及 sEH 在动脉粥样硬化患者中的作用尚未得到评估。我们假设 VSMC 中的 sEH 在动脉粥样硬化和损伤诱导的新内膜形成中发挥关键作用。在这项研究中，通过免疫组织化学测定了人体尸检动脉粥样硬化斑块中 sEH 的表达。在培养的大鼠和人 VSMC 中，通过蛋白质印迹分析检查了血小板源性生长因子-BB (PDGF-BB) 诱导的表型转换标记和 sEH 表达。在 Sprague-Dawley 大鼠中，腺病毒介导的 sEH 过度表达或口服有效的 sEH 抑制剂后，进行颈动脉球囊损伤。 sEH 在人动脉粥样硬化斑块内内膜和中膜的 VSMC 中高表达。体外，PDGF-BB转录后上调VSMCs表达，促进细胞增殖和迁移；后一种效应可以通过 sEH 抑制剂很大程度上减弱。腺病毒介导的 sEH 过度表达可以模拟 PDGF-BB 的作用并诱导 VSMC 增殖和迁移。在体内，sEH 抑制剂导致大鼠颈动脉损伤模型中损伤诱导的新内膜形成显着减少。这些数据确定了 sEH 表达对动脉粥样硬化进展和损伤后血管重塑的影响，从而确定了 sEH 在 VSMC 表型调节和迁移中的新整合作用。阻断 sEH 活性可能是改善血管闭塞性疾病的潜在治疗方法。
Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing their biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMCs plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by Western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs after transcription and promoted cell proliferation and migration; the latter effect could be largely attenuated by an sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB and induce VSMC proliferation and migration. In vivo, the sEH inhibitor led to a significant decrease in injury-induced neointima formation in a rat carotid-artery injury model. These data establish the effect of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role for sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.