Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia Autonomous Region, 028002, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, PR China.
Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia Autonomous Region, 028002, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, PR China.
Exp Cell Res. 2021 Apr 15;401(2):112519. doi: 10.1016/j.yexcr.2021.112519. Epub 2021 Feb 23.
Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation.
The ApoE mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed.
NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5.
Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.
动脉粥样硬化（AS）是一种炎症性疾病，动脉粥样硬化斑块的形成在 AS 进展中起着关键作用。本研究旨在探讨 DNA 损伤激活的长链非编码 RNA（lncRNA）（NORAD）/微小 RNA-495-3p（miR-495-3p）/Krüppel 样因子 5（KLF5）轴对动脉粥样硬化斑块形成的影响。
用高脂饮食喂养 ApoE 小鼠构建 AS 小鼠模型，并对模型小鼠进行 NORAD、miR-495-3p 或 KLF5 的改变处理。评估小鼠主动脉组织中 NORAD、miR-495-3p 和 KLF5 的表达水平，并测定小鼠的炎症因子、氧化应激因子、内皮功能指数和血脂水平。评估小鼠主动脉组织中动脉粥样硬化斑块面积、脂质沉积面积、胶原纤维和 CD68 的表达情况。验证 NORAD 与 miR-495-3p 的调控关系，以及 miR-495-3p 与 KLF5 的靶向关系。
在动脉粥样硬化小鼠主动脉中，NORAD 和 KLF5 增加，而 miR-495-3p 减少。抑制 NORAD 或上调 miR-495-3p 可抑制动脉粥样硬化小鼠的炎症、氧化应激、内皮功能障碍、血脂水平、动脉粥样硬化斑块面积、胶原纤维和 CD68 的表达。上调 KLF5 可逆转上调 miR-495-3p 对动脉粥样硬化小鼠的作用。NORAD 是 miR-495-3p 的海绵，miR-495-3p 直接靶向 KLF5。
沉默 NORAD 可通过降低 KLF5 来升高 miR-495-3p，从而抑制动脉粥样硬化斑块的形成。本研究的结果可能有助于探索 AS 的分子机制。
