Rosiglitazone Attenuates Endothelin-1-Induced Vasoconstriction by Upregulating Endothelial Expression of Endothelin B Receptor
Rosiglitazone Attenuates Endothelin-1-Induced Vasoconstriction by Upregulating Endothelial Expression of Endothelin B Receptor
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DOI：
10.1161/hypertensionaha.110.150375
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发表时间：
2010-07-01
期刊：
影响因子：
8.3
通讯作者：
Wang, Nanping
中科院分区：
文献类型：
--
作者：
Tian, Jianwei;Wong, Wing Tak;Wang, Nanping
噻唑烷二酮类药物改善胰岛素抵抗和内皮功能障碍。然而，噻唑烷二酮类药物的血管保护作用的机制仍有待充分阐明。本研究旨在探讨罗格列酮对内皮素（ET）1的抗血管收缩作用的分子机制。罗格列酮处理小鼠腹主动脉24小时，通过钢丝肌造影术评估ET-1诱导的血管收缩。结果表明，罗格列酮减弱ET-1诱导的小鼠血管收缩，这种作用被ET-B受体（ETBR）拮抗剂，NO合酶抑制剂，和内皮去除取消。通过使用北方印迹、实时RT-PCR、Western印迹和免疫组织化学技术，我们发现罗格列酮在mRNA和蛋白水平上上调小鼠动脉瘤和人血管内皮细胞中ETBR的表达。过氧化物酶体增殖物激活受体-γ拮抗剂阻止了ETBR的诱导。荧光素酶报告基因检测显示罗格列酮增强ETBR基因启动子活性。此外，染色质免疫沉淀试验表明过氧化物酶体增殖物激活受体-γ可以直接结合ETBR基因启动子。此外，罗格列酮在体内治疗也减弱了ET-1诱导的血管收缩，并增加了小鼠肠系膜动脉和肠系膜动脉中ETBR的表达。总之，这些结果表明，罗格列酮通过上调内皮ETBR（过氧化物酶体增殖物激活受体-γ直接靶点）减弱ET-1诱导的血管收缩。（高血压。2010; 56：129-135）。
Thiazolidinediones improve insulin resistance and endothelial dysfunction. However, the mechanisms underlying the vasoprotective effects of thiazolidinediones remain to be fully elucidated. The present study aimed to examine the molecular mechanism for the anti-vasoconstrictive effects of rosiglitazone in response to endothelin (ET) 1. Mouse aortas were treated with rosiglitazone for 24 hours, and ET-1-induced vasoconstriction was assessed by wire myography. The results showed that rosiglitazone attenuated ET-1-induced contraction in mouse aortas; this effect was abolished by ET-B receptor (ETBR) antagonist, NO synthase inhibitor, and by the removal of endothelium. By using Northern blotting, real-time RT-PCR, Western blotting, and immunohistochemical techniques, we found that rosiglitazone upregulated expression of ETBR at both mRNA and protein levels in mouse aortas and human vascular endothelial cells. The induction of ETBR was prevented by peroxisome proliferator-activated receptor-gamma antagonism. Luciferase reporter assay showed that rosiglitazone enhanced ETBR gene promoter activity. Furthermore, chromatin immunoprecipitation assays demonstrated that peroxisome proliferator-activated receptor-gamma can directly bind to ETBR gene promoter. Furthermore, in vivo treatment with rosiglitazone also attenuated the ET-1-induced vasoconstrictions and increased the ETBR expression in mouse aortas and mesenteric arteries. In conclusion, these results demonstrate that rosiglitazone attenuated ET-1-induced vasoconstriction through the upregulation of endothelial ETBR, which is a peroxisome proliferator-activated receptor-gamma direct target. (Hypertension. 2010; 56: 129-135.)