Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice.
Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice.
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DOI：
10.1097/ccm.0000000000001629
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发表时间：
2016-08
影响因子：
8.8
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Chu M;Qin S;Wu R;Zhou X;Tang X;Zhang S;Zhao Q;Wang H;Liu Y;Han X;Xiao J;Li X;Zhang C
脓毒症是一个严重的全球性健康问题，总死亡率为30%，其中血管损伤是主要的原因。本研究旨在探讨内毒素血管壁microRNA的表达谱及其在脓毒症相关血管损伤中的作用。前瞻性随机研究实验室研究雄性C57 BL/6小鼠，平均体重26.5 ±1.8g。通过脂多糖（LPS）注射（20 mg/kg，ip）（Sigma）在小鼠中诱导内毒素血症（25-27）。对照组小鼠腹腔注射等量生理盐水（500 μl）。另一亚组小鼠腹腔注射高剂量LPS（30 mg/kg）诱导内毒素相关性死亡。测定内毒素（LPS）诱导的小鼠胰岛中miRNA的表达谱。结果表明，内毒素诱导的小鼠动脉组织中存在一些microRNA的异常表达。其中，内皮细胞富集/特异性miR-126 a-3 p a-3 p在内毒素小鼠动脉、脓毒症人血管以及从内毒素小鼠分离或用LPS处理的血管内皮细胞中显著下调。miR-126 a-3 p的下调是通过抑制krüppel样因子2（KLF 2）的表达而发生的，而KLF 2的过表达可通过Ad-KLF 2抑制KLF 2的表达。miR-126 a-3 p在内皮细胞中的下调导致细胞凋亡增加、增殖和迁移减少，而miR-126 a-3 p模拟物可抑制这些变化。在体内，通过慢病毒过表达miR-126 a-3 p（LV-miR-126 a-3 p）减轻了内毒素血症诱导的内皮功能和血管通透性损伤。我们发现SPRED 1和VCAM-1是miR-126 a-3 p介导的内毒素血症效应的两个直接靶基因。最后，过表达miR-126 a-3 p可显著提高内毒素小鼠的存活率。这些结果表明，血管microRNA如miR-126 a-3 p可能代表了内毒素血症诱导的血管损伤和内毒素死亡的新机制和新的治疗靶点。
Sepsis poses a serious global health problem with an overall mortality rate of 30%, in which the vascular Injury is a major contributor of. The study is to determine the expression profile of microRNAs in endotoxic vascular walls and their potential roles in sepsis-related vascular injury. Prospective randomized study Laboratory investigation Male C57BL/6 mice, average weight 26.5 ±1.8g. Endotoxemia was induced in mice via lipopolysaccharide (LPS) injection (20 mg/kg, ip) (Sigma) (25-27). The control mice were injected with the same amount of saline (500 μl, ip). In a sub-group of mice, a high dose of LPS (30mg/kg, ip) was applied to induce endotoxin-related death. The miRNA expression profiles in aortas from lipopolysaccharide (LPS)-induced endotoxic mice were determined. The result demonstrated that some microRNAs were aberrantly expressed in endotoxic mouse arteries. Among them, the endothelial cell enriched/specific miR-126a-3p a-3p was significantly down-regulated in endotoxic mouse arteries, septic human vessels, as well as vascular endothelial cells isolated from endotoxic mice or treated with LPS. The down-regulation of miR-126a-3p occurred at transcriptional level via the decreased expression of krüppel-like factor 2 (KLF2), which could be inhibited by KLF2 over-expression via Ad-KLF2. The down-regulation of miR-126a-3p in endothelial cells resulted in the increased apoptosis, and decreased proliferation and migration, which were inhibited by miR-126a-3p mimics. In vivo, over-expression of miR-126a-3p via lentivirus (LV-miR-126a-3p) attenuated endotoxemia-induced injuries on endothelial function and vascular permeability. We found that SPRED1 and VCAM-1 were two direct target genes of miR-126a-3p related to miR-126a-3p-mediated effects in endotoxemia. Finally, the survival rate of endotoxic mice was significantly increased by the over-expression of miR-126a-3p. The results suggest that vascular microRNAs such as miR-126a-3p may represent novel mechanisms and new therapeutic targets for endotoxemia-induced vascular injury and endotoxic mortality.