微小 RNA-24 通过激活 Nrf2/Ho-1 信号通路抑制血管损伤引起的氧化应激。

MicroRNA-24 inhibits the oxidative stress induced by vascular injury by activating the Nrf2/Ho-1 signaling pathway.

机构信息

Central Laboratory, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China; Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China; Yichang Key Laboratory of Ischemic Cardiovascular and Cerebrovascular Disease Translational Medicine, China.

Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China; Yichang Key Laboratory of Ischemic Cardiovascular and Cerebrovascular Disease Translational Medicine, China.

出版信息

Atherosclerosis. 2019 Nov;290:9-18. doi: 10.1016/j.atherosclerosis.2019.08.023. Epub 2019 Sep 9.

DOI:10.1016/j.atherosclerosis.2019.08.023

PMID:31539718

Abstract

BACKGROUND AND AIMS

The process of endothelial repair in diabetic patients after stent implantation was significantly delayed compared with that in non-diabetic patients, and oxidative stress is increasingly considered to be relevant to the pathogenesis of diabetic endothelial repair. However, the mechanisms linking diabetes and reendothelialization after vascular injury have not been fully elucidated. The aim of this study was to evaluate the effect of microRNA-24 (miR-24) up-regulation in delayed endothelial repair caused by oxidative stress after balloon injury in diabetic rats.

METHODS

In vitro, vascular smooth muscle cells (VSMCs) isolated from the thoracic aorta were stimulated with high glucose (HG) after miR-24 recombinant adenovirus (Ad-miR-24-GFP) transfection for 3 days. In vivo, diabetic rats induced using high-fat diet (HFD) and low-dose streptozotocin (30 mg/kg) underwent carotid artery balloon injury followed by Ad-miR-24-GFP transfection for 20 min.

RESULTS

The expression of miR-24 was decreased in HG-stimulated VSMCs and balloon-injured carotid arteries of diabetic rats, which was accompanied by increased expression of Ogt and Keap1 and decreased expression of Nrf2 and Ho-1. Up-regulation of miR-24 suppressed VSMC oxidative stress induced by HG in vitro, and miR-24 up-regulation promoted reendothelialization in balloon-injured diabetic rats. The underlying mechanism was related to the activation of the Nrf2/Ho-1 signaling pathway, which subsequently suppressed intracellular reactive oxidative species (ROS) production and malondialdehyde (MDA) and NADPH oxidase (Nox) activity, and to the restoration of Sod and Gsh-px activation.

CONCLUSIONS

The up-regulation of miR-24 significantly promoted endothelial repair after balloon injury through inhibition of oxidative stress by activating the Nrf2/Ho-1 signaling pathway.

摘要

背景与目的

与非糖尿病患者相比，糖尿病患者支架植入术后内皮修复过程明显延迟，氧化应激被认为与糖尿病内皮修复的发病机制有关。然而，糖尿病与血管损伤后再内皮化之间的联系机制尚未完全阐明。本研究旨在评估微 RNA-24（miR-24）上调对糖尿病大鼠球囊损伤后氧化应激引起的内皮修复延迟的影响。

方法

体外，将胸主动脉分离的血管平滑肌细胞（VSMCs）在 miR-24 重组腺病毒（Ad-miR-24-GFP）转染后用高糖（HG）刺激 3 天。体内，使用高脂肪饮食（HFD）和低剂量链脲佐菌素（30mg/kg）诱导糖尿病大鼠，然后进行颈动脉球囊损伤，再进行 20 分钟 Ad-miR-24-GFP 转染。

结果

HG 刺激的 VSMCs 和糖尿病大鼠球囊损伤的颈动脉中 miR-24 的表达降低，同时 Ogt 和 Keap1 的表达增加，Nrf2 和 Ho-1 的表达减少。miR-24 的上调抑制了体外 HG 诱导的 VSMC 氧化应激，miR-24 的上调促进了球囊损伤的糖尿病大鼠的再内皮化。其潜在机制与 Nrf2/Ho-1 信号通路的激活有关，随后抑制了细胞内活性氧（ROS）的产生以及丙二醛（MDA）和 NADPH 氧化酶（Nox）的活性，并恢复了 Sod 和 Gsh-px 的激活。