Essential Role of MicroRNA-155 in Regulating Endothelium-Dependent Vasorelaxation by Targeting Endothelial Nitric Oxide Synthase
Essential Role of MicroRNA-155 in Regulating Endothelium-Dependent Vasorelaxation by Targeting Endothelial Nitric Oxide Synthase
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MicroRNA-155 通过靶向内皮一氧化氮合酶调节内皮依赖性血管舒张的重要作用
DOI：
10.1161/hypertensionaha.112.197301
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发表时间：
2012-12-01
期刊：
影响因子：
8.3
通讯作者：
Zhou, Jia-Guo
中科院分区：
文献类型：
--
作者：
Sun, Hai-Xiang;Zeng, De-Yi;Zhou, Jia-Guo
内皮型一氧化氮合酶（eNOS）产生的一氧化氮在维持心血管稳态中起着重要作用。在各种病理条件下，eNOS的异常表达有助于内皮功能障碍和心血管疾病的发生。据报道，多种病理刺激主要通过调节几种细胞质蛋白与eNOS mRNA 3 '非翻译区顺式作用序列的结合而降低eNOS mRNA的稳定性，从而降低eNOS表达。然而，详细的机制仍然难以捉摸。由于microRNAs通过结合其靶mrna的3 '非翻译区来抑制基因表达，因此microRNAs可能是eNOS表达的重要转录后调节剂。在这里，我们提供的证据表明eNOS是miR-155的直接靶点。miR-155过表达减少，而miR-155抑制增加，人脐静脉内皮细胞中eNOS表达和NO产生以及乙酰胆碱诱导的人乳腺内动脉内皮依赖性血管松弛。炎性细胞因子包括肿瘤坏死因子-&agr；miR-155表达增加。miR-155逆转肿瘤坏死因子-&agr的抑制作用诱导eNOS表达下调和内皮依赖性血管舒张损伤。此外，我们观察到辛伐他汀降低肿瘤坏死因子-&agr；-诱导miR-155上调，改善肿瘤坏死因子-&agr的作用；eNOS表达和内皮依赖性血管舒张。辛伐他汀通过干扰甲羟戊酸-香叶酰-焦磷酸- rhoa信号通路降低miR-155的表达。这些发现表明，miR-155是eNOS表达和内皮依赖性血管松弛的重要调节因子。抑制miR-155可能是改善心血管疾病发展过程中内皮功能障碍的一种新的治疗方法。
Nitric oxide generated by endothelial nitric oxide synthase (eNOS) plays an important role in maintaining cardiovascular homeostasis. Under various pathological conditions, abnormal expression of eNOS contributes to endothelial dysfunction and the development of cardiovascular diseases. A variety of pathological stimuli has been reported to decrease eNOS expression mainly through decreasing eNOS mRNA stability by regulating the binding of several cytosolic proteins to the cis-acting sequences within eNOS mRNA 3′ untranslated regions. However, the detailed mechanisms remain elusive. Because microRNAs inhibit gene expression through binding to the 3′ untranslated regions of their target mRNAs, microRNAs may be the important posttranscriptional modulators of eNOS expression. Here, we provided evidence that eNOS is a direct target of miR-155. Overexpression of miR-155 decreased, whereas inhibition of miR-155 increased, eNOS expression and NO production in human umbilical vein endothelial cells and acetylcholine-induced endothelium-dependent vasorelaxation in human internal mammary arteries. Inflammatory cytokines including tumor necrosis factor-&agr; increased miR-155 expression. Inhibition of miR-155 reversed tumor necrosis factor-&agr;–induced downregulation of eNOS expression and impairment of endothelium-dependent vasorelaxation. Moreover, we observed that simvastatin attenuated tumor necrosis factor-&agr;–induced upregulation of miR-155 and ameliorated the effects of tumor necrosis factor-&agr; on eNOS expression and endothelium-dependent vasodilation. Simvastatin decreased miR-155 expression through interfering mevalonate-geranylgeranyl-pyrophosphate-RhoA signaling pathway. These findings indicated that miR-155 is an essential regulator of eNOS expression and endothelium-dependent vasorelaxation. Inhibition of miR-155 may be a new therapeutic approach to improve endothelial dysfunction during the development of cardiovascular diseases.