Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China.
Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China.
Exp Cell Res. 2021 Mar 1;400(1):112507. doi: 10.1016/j.yexcr.2021.112507. Epub 2021 Feb 3.
Macrophage mediated inflammation and foam cell formation play crucial roles in the development of atherosclerosis. MiR-375 is a small noncoding RNA that significantly implicated in multiple tumor regulation and has been emerged as a novel biomarker for type 2 diabetes. However, the exact role of miR-375 on macrophage activation remains unknown. In the present study, we observed that miR-375 expression showed an up-regulated expression in atherosclerotic aortas, as well as in bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs) isolated from ApoE deficiency mice and was gradually increased followed the Ox-LDL treated time. Functionally, miR-375 inhibition significantly decreased foam cell formation accompanied by up-regulated genes expression involved in cholesterol efflux but reduced genes expression implicated in cholesterol influx. Moreover, miR-375 silencing increased resolving M2 macrophage but reduced pro-inflammatory M1 macrophage markers expression. Such above effects can be reversed by miR-375 overexpression. Mechanistically, we noticed that miR-375 knockdown promoted KLF4 expression which was required for the ameliorated effect of miR-375 silencing on macrophage activation. Importantly, the consistent results in mRNA expression of M1 and M2 markers were observed in vivo, and miR-375ApoE mice significant decreased atherosclerotic lesions in the whole aorta and aortic sinus. Taken together, these evidences suggested that miR-375 knockdown attenuated macrophage activation partially through activation of KLF4-dependent mechanism.
巨噬细胞介导的炎症和泡沫细胞形成在动脉粥样硬化的发展中起着至关重要的作用。miR-375 是一种小的非编码 RNA，在多种肿瘤调控中具有重要意义，已成为 2 型糖尿病的一种新型生物标志物。然而，miR-375 对巨噬细胞激活的确切作用尚不清楚。在本研究中，我们观察到 miR-375 在动脉粥样硬化主动脉以及从 ApoE 缺陷小鼠分离的骨髓来源巨噬细胞 (BMDM) 和小鼠腹腔巨噬细胞 (MPM) 中呈上调表达，并且随着 Ox-LDL 处理时间的延长而逐渐增加。功能上，miR-375 抑制显著减少泡沫细胞形成，同时上调胆固醇流出涉及的基因表达，但降低胆固醇内流涉及的基因表达。此外，miR-375 沉默增加了促分解的 M2 巨噬细胞，但减少了促炎的 M1 巨噬细胞标志物的表达。这种上述作用可以通过 miR-375 的过表达逆转。机制上，我们注意到 miR-375 敲低促进了 KLF4 的表达，这是 miR-375 沉默对巨噬细胞激活改善作用所必需的。重要的是，在体内观察到 M1 和 M2 标志物的 mRNA 表达一致，miR-375ApoE 小鼠在整个主动脉和主动脉窦中的动脉粥样硬化病变明显减少。总之，这些证据表明，miR-375 敲低通过激活 KLF4 依赖性机制部分减轻了巨噬细胞的激活。
