MicroRNA‑126 inhibits endothelial permeability and apoptosis in apolipoprotein E‑knockout mice fed a high‑fat diet.
MicroRNA‑126 inhibits endothelial permeability and apoptosis in apolipoprotein E‑knockout mice fed a high‑fat diet.
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MicroRNA™126 抑制高脂饮食的载脂蛋白 E™ 敲除小鼠的内皮通透性和细胞凋亡
DOI：
10.3892/mmr.2017.6952
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发表时间：
2017-09
影响因子：
3.4
通讯作者：
Zhu HQ
中科院分区：
文献类型：
--
作者：
Cheng XW;Wan YF;Zhou Q;Wang Y;Zhu HQ
内皮功能障碍和细胞凋亡在动脉粥样硬化（AS）的发生和进展中发挥着关键作用。 AS 已被证明与高脂肪饮食有关，这可能会增加内皮通透性和细胞凋亡；然而，AS 发展的确切机制仍然知之甚少。 MicroRNA (miRNA) 对于心血管疾病的调节至关重要，并且失调的 miRNA 与 AS 有关。本研究调查了 miRNA (miR)-126 是否通过靶向转化生长因子 β (TGFβ)（一种控制细胞增殖和凋亡的分泌蛋白）来调节高脂肪饮食诱导的内皮通透性和细胞凋亡。在本研究中，载脂蛋白 E (apoE)−/− 小鼠被喂以高脂肪饮食，以建立 AS 模型。小鼠皮下注射 miR-126 模拟物、miR-126 antagomir 或对照 miRNA。使用逆转录定量聚合酶链反应评估 miR-126 表达，并使用荧光测定法评估 caspase-3 活性。还探讨了 miR-126 对主动脉内膜内皮通透性的影响。采用蛋白质印迹和免疫组织化学分析研究 miR-126 对 B 细胞淋巴瘤 2 (Bcl-2) 和转化生长因子 (TGF) β 蛋白表达水平的影响。此外，进行荧光素酶测定以验证TGFβ是否可能是miR-126的直接靶基因。在载脂蛋白 E 敲除小鼠中，高脂肪饮食降低了 miR-126 表达并诱导细胞凋亡（通过 caspase-3 活性上调来确定）。 miR-126 antagomir 可增加高脂饮食小鼠的内皮通透性和细胞凋亡。相比之下，miR-126 模拟物减弱了内皮通透性和细胞凋亡。在喂食高脂肪饮食的小鼠中，miR-126 的减少与 Bcl-2 蛋白表达水平的降低和 TGFβ 的增加有关。此外，本研究表明，miR-126 与 TGFβ mRNA 3'非翻译区结合后可降低 TGFβ 表达。目前的研究证明了 miR-126 在 AS 中的作用，并确定 TGFβ 是 miR-126 的直接靶标。此外，本研究表明 miR-126 有助于内皮细胞通透性和细胞凋亡，并表明 TGFβ 的下调可能参与 miR-126 作用的分子机制。因此，miR-126 可能具有作为治疗 AS 的新治疗靶点的潜力。
Endothelial dysfunction and apoptosis have key roles in the initiation and progression of atherosclerosis (AS). AS has been demonstrated to be associated with a high-fat diet, which may increase endothelial permeability and apoptosis; however, the exact mechanisms underlying the development of AS remain poorly understood. MicroRNAs (miRNAs) are vital for the regulation of cardiovascular disease, and dysregulated miRNAs have been implicated in AS. The present study investigated whether miRNA (miR)-126 regulates high-fat diet-induced endothelial permeability and apoptosis by targeting transforming growth factor β (TGFβ), a secreted protein that controls cellular proliferation and apoptosis. In the present study, apolipoprotein E (apoE)−/− mice were fed a high-fat diet in order to establish a model of AS. Mice were subcutaneously injected with a miR-126 mimic, a miR-126 antagomir or control miRNA. Reverse transcription-quantitative polymerase chain reaction was used to assess miR-126 expression, and a fluorometric assay was used to evaluate caspase-3 activity. The effects of miR-126 on the endothelial permeability of the aortic intima were also explored. Western blotting and immunohistochemical analysis were used to investigate the effects of miR-126 on B-cell lymphoma-2 (Bcl-2) and transforming growth factor (TGF) β protein expression levels. Furthermore, a luciferase assay was performed to verify whether TGFβ may be a direct target gene of miR-126. In apolipoprotein E-knockout mice, a high-fat diet reduced miR-126 expression and induced apoptosis as determined by the upregulation of caspase-3 activity. A miR-126 antagomir increased endothelial permeability and apoptosis in mice fed a high-fat diet. By contrast, an miR-126 mimic attenuated endothelial permeability and apoptosis. The reduction in miR-126 was associated with a reduction in protein expression levels of Bcl-2 and an increase of TGFβ in mice fed a high-fat diet. In addition, the present study demonstrated that miR-126 reduced TGFβ expression following binding to the 3′-untranslated region of TGFβ mRNA. The current study demonstrated a role for miR-126 in AS and identified TGFβ as a direct target of miR-126. Furthermore, the present study demonstrated that miR-126 contributed to endothelial permeability and apoptosis, and suggested that the downregulation of TGFβ may be involved in the molecular mechanisms underlying the actions of miR-126. miR-126 may therefore have potential as a novel therapeutic target for the treatment of AS.
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影响因子：
3.1
作者：
Sun X;Zhang M;Sanagawa A;Mori C;Ito S;Iwaki S;Satoh H;Fujii S
通讯作者：
Fujii S
影响因子：
13.6
作者：
Andreou I;Sun X;Stone PH;Edelman ER;Feinberg MW
通讯作者：
Feinberg MW
影响因子：
20.1
作者：
Climent, Montserrat;Quintavalle, Manuela;Elia, Leonardo
通讯作者：
Elia, Leonardo
影响因子：
29
作者：
Kraakman, Michael J.;Kammoun, Helene L.;Febbraio, Mark A.
通讯作者：
Febbraio, Mark A.
影响因子：
37.8
作者：
Jakob, Philipp;Doerries, Carola;Landmesser, Ulf
通讯作者：
Landmesser, Ulf