Inhibition of miR-21 alleviated cardiac perivascular fibrosis via repressing EndMT in T1DM
Inhibition of miR-21 alleviated cardiac perivascular fibrosis via repressing EndMT in T1DM
复制标题
抑制 miR-21 通过抑制 T1DM 中的 EndMT 减轻心脏血管周围纤维化
DOI：
10.1111/jcmm.14800
复制
发表时间：
2019-11-03
影响因子：
5.3
通讯作者：
Tu, Xin
中科院分区：
文献类型：
--
作者：
Li, Qianqian;Yao, Yufeng;Tu, Xin
在1型和2型糖尿病中，心脏纤维化增加、僵硬和相关的舒张功能障碍可能是糖尿病心肌病的最早病理现象。内皮细胞间质转化（endothelial-mesenchymal transition，EndMT）是糖尿病心脏中一种重要的细胞学现象，可导致心脏成纤维细胞（cardiac fibroblasts，CF）和心脏纤维化的发生。本文旨在探讨miR-21调控糖尿病心肌病EndMT和心肌血管周围纤维化的分子机制。在体内，高脂血症上调miR-21的mRNA水平，加重心功能不全和胶原沉积。通过抑制miR-21，改善心脏功能和减少胶原沉积，病情得以恢复。miR-21抑制通过抑制EndMT和上调SMAD 7而激活p-SMAD 2和p-SMAD 3来降低心脏血管周围纤维化。在体外，高糖（HG）上调miR-21并诱导EC中的EndMT，而抑制miR-21可降低EndMT。在miR-21 5 '-UTR中发现了一个高度保守的NF-κ B B结合位点。在EC中，SMAD 7直接受miR-21调控。结论：NF-κ B B/miR-21/SMAD 7通路调控了T1 DM心肌病中EndMT的表达，提示NF-κ B/miR-21/SMAD 7通路可能是治疗心肌血管周围纤维化的潜在靶点。
In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial-mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR-21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up-regulated the mRNA level of miR-21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR-21 following with improving cardiac function and decreasing collagen deposition. miR-21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up-regulating SMAD7 whereas activating p-SMAD2 and p-SMAD3. In vitro, high glucose (HG) up-regulated miR-21 and induced EndMT in ECs, which was decreased by inhibition of miR-21. A highly conserved binding site of NF-kappa B located in miR-21 5 '-UTR was identified. In ECs, SMAD7 is directly regulated by miR-21. In conclusion, the pathway of NF-kappa B/miR-21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.