Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K
Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K
复制标题
miR-185 的内源性减少通过靶向组织蛋白酶 K 加速心肌梗死后小鼠的心功能恢复
DOI：
10.1111/jcmm.14016
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发表时间：
2019-02-01
影响因子：
5.3
通讯作者：
Bai, Yong-Ping
中科院分区：
文献类型：
--
作者：
Li, Chuan-Chang;Qiu, Xue-Ting;Bai, Yong-Ping
急性冠状动脉综合征（ACS）患者发生心肌梗塞（MI）后，血管生成对于重建存活心肌的血液供应至关重要。 MicroRNA 被认为是内皮功能的重要表观遗传调节因子。本研究的目的是确定 microRNA 在血管生成中的作用。通过高通量 RNA 测序，包括 miR-185-5p 在内的 18 种循环 microRNA 在 ACS 患者血浆中的表达存在差异。通过荧光原位杂交和定量 RT-PCR 测定，在心肌梗死后的小鼠心脏中以及在缺氧条件下培养的人脐静脉内皮细胞 (HUVEC) 中，miR-185-5p 的表达水平显着降低。计算预测和荧光素酶报告基因活性的证据表明组织蛋白酶 K (CatK) mRNA 是 miR-185-5p 的靶标。在 HUVEC 中，miR-185-5p 模拟物在缺氧条件下抑制细胞增殖、迁移和管形成，而 miR185-5p 抑制剂则起到相反的作用。此外，CatK基因过表达消除了miR185-5p上调对HUVEC细胞功能的抑制作用，而腺病毒介导的CatK基因沉默消除了缺氧下HUVECs的这些增强作用。体内研究表明，通过agomir输注获得的miR-185-5p功能可下调CatK基因表达，损害血管生成并延迟MI后小鼠心脏功能的恢复。 miR-185-5p 激动剂的这些作用通过 MI 小鼠体内 CatK 的敲除得到反映。缺氧诱导的内皮细胞中 miR-185-5p 的内源性减少会增加 CatK 基因的表达，从而促进血管生成并加速 MI 后小鼠心脏功能的恢复。
Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR185-5p up-regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain-function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.