Soluble Epoxide Hydrolase Inhibition Protected against Angiotensin II-induced Adventitial Remodeling.
Soluble Epoxide Hydrolase Inhibition Protected against Angiotensin II-induced Adventitial Remodeling.
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可溶性环氧化物水解酶抑制剂可预防血管紧张素 II 诱导的外膜重塑
DOI：
10.1038/s41598-017-07512-1
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发表时间：
2017-07-31
影响因子：
4.6
通讯作者：
Wang DW
中科院分区：
文献类型：
--
作者：
Zhou C;Huang J;Li Q;Nie J;Xu X;Wang DW
环氧二十碳三烯酸（Epoxyeicosatrienoicacids，ESTs）是花生四烯酸衍生的细胞色素P450表氧化酶的代谢产物，在维持心血管稳态方面具有重要的生物学活性。可溶性环氧化物水解酶（sEH）将雌二醇水解为生物活性较低的二羟基二十碳三烯酸。然而，sEH抑制对外膜重塑的影响仍不确定。在本研究中，C57 BL/6 J小鼠通过持续2周的Ang II输注建立外膜重塑模型，在此之前通过灌胃给予sEH抑制剂1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU）。采用组织学、免疫荧光、钙离子显像、CCK-8和transwell法检测血管外膜重构。结果显示，血管紧张素Ⅱ可明显诱导主动脉外膜血管壁增厚、胶原沉积、α-SMA和PCNA表达。有趣的是，这些损伤被TPPU给药减弱。此外，TPPU预处理明显阻止Ang II诱导的原代外膜成纤维细胞活化，其特征在于通过Ca 2 +-calcineurin/NFATc 3信号通路在体外分化、增殖、迁移和胶原合成。总之，我们的研究结果表明，抑制sEH可以被认为是一种新的治疗策略，以治疗外膜重塑相关的疾病。
Epoxyeicosatrienoic acids (EETs), the metabolites of cytochrome P450 epoxygenases derived from arachidonic acid, exert important biological activities in maintaining cardiovascular homeostasis. Soluble epoxide hydrolase (sEH) hydrolyzes EETs to less biologically active dihydroxyeicosatrienoic acids. However, the effects of sEH inhibition on adventitial remodeling remain inconclusive. In this study, the adventitial remodeling model was established by continuous Ang II infusion for 2 weeks in C57BL/6 J mice, before which sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered by gavage. Adventitial remodeling was evaluated by histological analysis, western blot, immunofluorescent staining, calcium imaging, CCK-8 and transwell assay. Results showed that Ang II infusion significantly induced vessel wall thickening, collagen deposition, and overexpression of α-SMA and PCNA in aortic adventitia, respectively. Interestingly, these injuries were attenuated by TPPU administration. Additionally, TPPU pretreatment overtly prevented Ang II-induced primary adventitial fibroblasts activation, characterized by differentiation, proliferation, migration, and collagen synthesis via Ca2+-calcineurin/NFATc3 signaling pathwayin vitro. In summary, our results suggest that inhibition of sEH could be considered as a novel therapeutic strategy to treat adventitial remodeling related disorders.
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影响因子：
3.7
作者：
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影响因子：
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影响因子：
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通讯作者：
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