MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.
MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.
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MiR-302a 通过抑制内皮细胞中的核因子-γ B 通路来限制血管炎症
DOI：
10.3389/fcell.2021.682574
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang TT
中科院分区：
文献类型：
--
作者：
Yuan JN;Hong Y;Ma ZL;Pang RP;Lei QQ;Lv XF;Zhou JG;Huang H;Zhang TT
内皮细胞的炎症反应加速了各种血管疾病。microRNA（miRNAs）参与炎症过程中的多种细胞过程。在本研究中，我们发现miR-302 a是内皮细胞中血管炎症的有效抑制剂。结果显示，miR-302 a在脂多糖（LPS）诱导的小鼠模型和血管炎性疾病患者中表现出较低的水平。miR-302的遗传单倍不足加重了LPS诱导的小鼠血管炎症反应，而miR-302 a的过表达减轻了小鼠血管炎症反应。此外，过表达miR-302 a可抑制内皮细胞粘附因子的合成和分泌，抑制单核细胞与内皮细胞的粘附。在分子机制研究中，我们发现miR-302 a主要通过调节内皮细胞核因子-κ B（NF-κB）通路来减轻血管炎症。结果表明，白细胞介素1受体相关激酶4（IRAK 4）和锌指蛋白91（ZFP 91）是miR-302 a的结合靶点。MiR-302 a通过靶向IRAK 4抑制IκB激酶复合物β（IKKβ）的磷酸化和κBα（IκBα）的抑制剂来阻止NF-κB的核转位。此外，miR-302 a通过与ZFP 91直接结合下调NF-κB的表达。这些结果表明，miR-302 a通过NF-κB通路负性调节内皮细胞的炎症反应，可能成为缓解血管炎症的新靶点。
The inflammatory response of endothelial cells accelerates various vascular diseases. MicroRNAs (miRNAs) participate in diverse cellular processes during inflammation. In the present study, we found that miR-302a is an effective suppressor of vascular inflammation in endothelial cells. It was revealed that miR-302a exhibited a lower level in a lipopolysaccharide (LPS)-induced mouse model and in patients with vascular inflammatory disease. Genetic haploinsufficiency of miR-302 aggravated the LPS-induced vascular inflammatory response in mice, and overexpression of miR-302a attenuated vascular inflammation in mice. Furthermore, overexpression of miR-302a inhibited the synthesis and secretion of adhesion factors in endothelial cells, and suppressed the adhesion of monocytes to endothelium. In the study of molecular mechanism, we found that miR-302a relieved vascular inflammation mainly by regulating the nuclear factor kappa-B (NF-κB) pathway in endothelial cells. The results showed that interleukin-1 receptor-associated kinase4 (IRAK4) and zinc finger protein 91 (ZFP91) were the binding targets of miR-302a. MiR-302a prevented the nuclear translocation of NF-κB by inhibiting phosphorylation of IκB kinase complex β (IKKβ) and inhibitors of κBα (IκBα) via targeting IRAK4. In addition, miR-302a downregulated the expression of NF-κB by directly binding with ZFP91. These findings indicate that miR-302a negatively regulates inflammatory responses in the endothelium via the NF-κB pathway and it may be a novel target for relieving vascular inflammation.