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MicroRNA-216a Promotes Endothelial Inflammation by Smad7/IκBα Pathway in Atherosclerosis
Disease Markers ( IF 3.464 ) Pub Date : 2020-11-18 , DOI: 10.1155/2020/8864322
Shujun Yang 1, 2 , Yu Chen 1 , Xuenan Mi 1 , Shuyuan Zhang 1 , Yunyun Yang 1 , Rutai Hui 1 , Weili Zhang 1
Affiliation  

Background. The endothelium is the first line of defence against harmful microenvironment risks, and microRNAs (miRNAs) involved in vascular inflammation may be promising therapeutic targets to modulate atherosclerosis progression. In this study, we aimed to investigate the mechanism by which microRNA-216a (miR-216a) modulated inflammation activation of endothelial cells. Methods. A replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established, and population-doubling levels (PDLs) were defined during passages. PDL8 HUVECs were transfected with miR-216a mimics/inhibitor or small interfering RNA (siRNA) of SMAD family member 7 (Smad7). Real-time PCR and Western blot assays were performed to detect the regulatory role of miR-216a on Smad7 and NF-κB inhibitor alpha (IκBα) expression. The effect of miR-216a on adhesive capability of HUVECs to THP-1 cells was examined. MiR-216a and Smad7 expression in vivo were measured using human carotid atherosclerotic plaques of the patients who underwent carotid endarterectomy (). Results. Luciferase assays showed that Smad7 was a direct target of miR-216a. Smad7 mRNA expression, negatively correlated with miR-216a during endothelial aging, was downregulated in senescent PDL44 cells, compared with young PDL8 HUVECs. MiR-216a markedly increased endothelial inflammation and adhesive capability to monocytes in PDL8 cells by promoting the phosphorylation and degradation of IκBα and then activating NF-κB signalling pathway. The effect of miR-216a on endothelial cells was consistent with that blocked Smad7 by siRNAs. When inhibiting endogenous miR-216a, the Smad7/IκBα expression was rescued, which led to decreased endothelial inflammation and monocytes recruitment. In human carotid atherosclerotic plaques, Smad7 level was remarkably decreased in high miR-216a group compared with low miR-216a group. Moreover, miR-216a was negatively correlated with Smad7 and IκBα levels and positively correlated with interleukin 1 beta (IL1β) expression in vivo. Conclusion. In summary, our findings suggest a new mechanism of vascular endothelial inflammation involving Smad7/IκBα signalling pathway in atherosclerosis.

中文翻译:

MicroRNA-216a 通过 Smad7/IκBα 通路促进动脉粥样硬化的内皮炎症

背景。内皮是抵御有害微环境风险的第一道防线,参与血管炎症的 microRNA (miRNA) 可能是调节动脉粥样硬化进展的有希望的治疗靶点。在这项研究中,我们旨在研究 microRNA-216a (miR-216a) 调节内皮细胞炎症激活的机制。方法。建立了人脐静脉内皮细胞(HUVECs)的复制衰老模型,并在传代过程中定义了群体倍增水平(PDLs)。用 SMAD 家族成员 7 (Smad7) 的 miR-216a 模拟物/抑制剂或小干扰 RNA (siRNA) 转染 PDL8 HUVEC。进行实时 PCR 和蛋白质印迹分析以检测 miR-216a 对 Smad7 和 NF- κ的调节作用B抑制剂α(IκBα 表达。检查了 miR-216a 对 HUVEC 对 THP-1 细胞的粘附能力的影响。使用接受颈动脉内膜切除术的患者的人颈动脉粥样硬化斑块测量体内MiR-216a 和 Smad7 的表达。)。 结果。荧光素酶测定显示 Smad7 是 miR-216a 的直接靶标。与年轻的 PDL8 HUVEC 相比,Smad7 mRNA 表达在内皮衰老过程中与 miR-216a 呈负相关,在衰老的 PDL44 细胞中下调。MiR-216a 通过促进IκBα的磷酸化和降解,然后激活 NF-κB信号通路PDL8细胞中内皮炎症和对单核细胞的粘附能力miR-216a 对内皮细胞的作用与 siRNA 阻断 Smad7 的作用一致。当抑制内源性 miR-216a 时,Smad7/I κ B α表达被挽救,这导致内皮炎症和单核细胞募集减少。在人颈动脉粥样硬化斑块中,与低miR-216a组相比,高miR-216a组的Smad7水平显着降低。此外,miR-216a 与 Smad7 和IκBα水平呈负相关,与体内白细胞介素1 β (IL1β ) 表达呈正相关。结论。总之,我们的研究结果提示了动脉粥样硬化中涉及 Smad7/I κ B α信号通路的血管内皮炎症的新机制。
更新日期:2020-11-18
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