Department of Cardiology, Fengxian District Central Hospital, Shanghai, China.
Department of Cardiology, Fengxian District Central Hospital, Shanghai, China.
Life Sci. 2021 Nov 1;284:119615. doi: 10.1016/j.lfs.2021.119615. Epub 2021 May 15.
Atherosclerosis (AS) is a multifocal, smoldering immune inflammatory disease of medium and large arteries driven by lipids. The aim of this study is to discuss the mechanism of microRNA-146a-3p (miR-146a-3p)/histone deacetylase 1 (HDAC1)/Krüppel-like factor 5 (KLF5)/inhibitors of kappa B α (IKBα) signal axis in plaque formation of AS mice.
ApoE mice were fed with high-fat feed for 12 weeks to establish AS mice model. The expression of miR-146a-3p, KLF5, HDAC1 and IKBα in aortic wall tissues of AS mice was tested. The targeting relationship between miR-146a-3p and HDAC1 was verified. AS mice were injected with miR-146a-3p antagomir or HDAC1 overexpression to verify the impacts of miR-146a-3p and HDAC1 on blood lipids and inflammatory factors in serum, aortic wall apoptotic cells, antioxidant stress capacity and the plaque area in AS mice. VECs proliferation and apoptosis were also measured in vitro.
miR-146a-3p and KLF5 were increased while HDAC1 and IKBα were reduced in aortic wall tissues of AS mice. miR-146a-3p directly targeted to HDAC1. Depletion of miR-146a-3p or restoration of HDAC1 was correlated to lower plasma lipid level, reduced inflammatory factors in serum, attenuated aortic wall apoptosis, increased antioxidant stress capacity and improved the stability of pathological plaque of AS mice. miR-146a-3p down-regulation or HDAC1 up-regulation promoted VECs proliferation and inhibited apoptosis.
Functional studies show that depleted miR-146a-3p advances HDAC1 and IKBα expression as well as inhibits KLF5 expression to facilitate the stability of pathological plaques in AS mice.
动脉粥样硬化（AS）是一种由脂质驱动的中大型动脉多灶性、潜伏性免疫炎症性疾病。本研究旨在探讨微小 RNA-146a-3p（miR-146a-3p）/组蛋白去乙酰化酶 1（HDAC1）/Krüppel 样因子 5（KLF5）/κB 抑制因子α（IKBα）信号轴在 AS 小鼠斑块形成中的作用机制。
用高脂饲料喂养载脂蛋白 E （ApoE） 小鼠 12 周建立 AS 小鼠模型。检测 AS 小鼠主动脉壁组织中 miR-146a-3p、KLF5、HDAC1 和 IKBα的表达。验证 miR-146a-3p 与 HDAC1 的靶向关系。向 AS 小鼠注射 miR-146a-3p 拮抗剂或 HDAC1 过表达载体，验证 miR-146a-3p 和 HDAC1 对 AS 小鼠血清中血脂和炎症因子、主动脉壁凋亡细胞、抗氧化应激能力和斑块面积的影响。还在体外测量了血管内皮细胞的增殖和凋亡。
AS 小鼠主动脉壁组织中 miR-146a-3p 和 KLF5 表达增加，而 HDAC1 和 IKBα 表达降低。miR-146a-3p 可直接靶向 HDAC1。miR-146a-3p 耗竭或 HDAC1 恢复与降低血浆脂质水平、减少血清炎症因子、减轻主动脉壁细胞凋亡、增加抗氧化应激能力和改善 AS 小鼠病理性斑块稳定性有关。miR-146a-3p 下调或 HDAC1 上调促进血管内皮细胞增殖，抑制凋亡。
功能研究表明，miR-146a-3p 耗竭可促进 HDAC1 和 IKBα 表达，抑制 KLF5 表达，从而促进 AS 小鼠病理性斑块的稳定性。
