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长链非编码 RNA-p21 通过调控 miR-221/SIRT1/Pcsk9 轴减轻动脉粥样硬化进展。

LincRNA-p21 alleviates atherosclerosis progression through regulating the miR-221/SIRT1/Pcsk9 axis.

机构信息

Thoracic & Cardiovascular Surgery, Huaihe Hospital of Henan University, Kaifeng, China.

School of Clinical Medicine, Henan University, Kaifeng, China.

出版信息

J Cell Mol Med. 2021 Oct;25(19):9141-9153. doi: 10.1111/jcmm.16771. Epub 2021 Sep 19.

DOI:10.1111/jcmm.16771
PMID:34541816
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8500963/
Abstract

Atherosclerosis (AS) is the main aetiology of coronary heart disease, cerebral infarction and peripheral vascular disease in humans. Long-noncoding RNA (LincRNA)-p21 has been reported to participate in the development of AS. Therefore, this study was designed to investigate the mechanism of LincRNA-p21 on suppressing the development of AS. We fed ApoE mice with a high-fat diet to induce an AS mouse model where the lesion area of AS and the extent of lipid deposition were measured. The binding of LincRNA-p21 and miR-221 or miR-221 and SIRT1 was measured using a dual luciferase reporter gene assay and RIP. Following loss- and gain- function assays, CCK8, EdU, Transwell assay and scratch test were performed to determine the biological processes of human aortic endothelial cells (HAECs). miR-221 was highly expressed while SIRT1 was poorly expressed in AS. LincRNA-p21 acted as a sponge for miR-221. miR-221 targeted and negatively regulated the expression of SIRT1. LincRNA-p21 promoted the deacetylation of Pcsk9 by SIRT1 by competitively binding to miR-221, whereby promoting HAEC proliferation, migration and tube formation. In conclusion, LincRNA-p21 acted as a molecular sponge for miR-221 to promote deacetylation of the promoter region of Pcsk9 by SIRT1, therefore preventing the development of AS.

摘要

动脉粥样硬化（AS）是人类冠心病、脑梗死和外周血管疾病的主要病因。长链非编码 RNA（LincRNA）-p21 已被报道参与 AS 的发展。因此，本研究旨在探讨 LincRNA-p21 抑制 AS 发展的机制。我们用高脂饮食喂养 ApoE 小鼠，诱导 AS 小鼠模型，测量 AS 病变面积和脂质沉积程度。使用双荧光素酶报告基因检测和 RIP 检测 LincRNA-p21 和 miR-221 或 miR-221 和 SIRT1 的结合。进行缺失和获得功能测定后，通过 CCK8、EdU、Transwell 测定和划痕试验来确定人主动脉内皮细胞（HAECs）的生物学过程。miR-221 在 AS 中高表达，而 SIRT1 低表达。LincRNA-p21 作为 miR-221 的海绵体。miR-221 靶向并负调控 SIRT1 的表达。LincRNA-p21 通过与 miR-221 竞争结合，促进 SIRT1 对 Pcsk9 的去乙酰化，从而促进 HAEC 的增殖、迁移和管形成。总之，LincRNA-p21 作为 miR-221 的分子海绵，促进 SIRT1 对 Pcsk9 启动子区域的去乙酰化，从而预防 AS 的发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f7/8500963/a66ebe15a443/JCMM-25-9141-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f7/8500963/a66ebe15a443/JCMM-25-9141-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f7/8500963/6a1be7b2d8b3/JCMM-25-9141-g002.jpg
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