Inhibition of MicroRNA-92 alleviates atherogenesis by regulation of macrophage polarization through targeting KLF4

• Published in: Journal of cardiology Vol. 79; no. 3; pp. 432 - 438
• Main Authors: Gao, Feng, Chen, Xueying, Xu, Banglong, Luo, Zhidan, Liang, Yi, Fang, Sihua, Li, Mengli, Wang, Xiaochen, Lin, Xianhe
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2022
• Subjects: Animals; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - prevention & control; KLF4; Kruppel-Like Factor 4 - metabolism; Macrophage Activation; Macrophage polarization; Macrophages - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miR-92; Plaque, Atherosclerotic; Macrophage polarization; KLF4; miR-92; Atherosclerosis
• ISSN: 0914-5087; 1876-4738
• DOI: 10.1016/j.jjcc.2021.10.015

•MiR-92 inhibition promoted macrophage polarization to M2 state in vitro and in vivo.•MiR-92 knockdown alleviated plaque size and increased stability.•KLF4 was required for miR-92 silencing-mediated macrophage polarization. Atherosclerosis is a chronic inflammatory disease in which macrophage polarization plays an important role in contribution to atherosclerotic plaque formation and stability. Here we tested the effect of miR-92 regulation on the development of atherosclerosis beyond tumorigenesis and explored the potential mechanism. In the present study, bone marrow derived macrophages (BMDMs), mouse peritoneal macrophages (MPMs), and human macrophages were used to test the expression of miR-92. Here we noticed miR-92 levels were enhanced in classic M1 macrophage but decreased in alternative M2 macrophage, respectively. In vitro, we demonstrated that macrophages transfected with miR-92 inhibitor attenuated proinflammatory cytokine secretion represented by polarized M1 markers but promoted anti-inflammatory state that was indicative of an M2 phenotype. Mechanistically, miR-92 was found to directly interact with KLF4 and we further identified a requirement role of KLF4 in mediating the effect of miR-92 silencing macrophage polarization. Concomitantly, miR-92 inhibition treated ApoE−/− mice promoted macrophage polarization toward alternative M2 macrophage, thus protecting against atherosclerotic plaque formation and preventing a vulnerable phenotype. miR-92 inhibition promoted alternative macrophage activation and attenuated atherosclerosis regression partially regulated in a KLF4-dependent manner, which indicated that miR-92/KLF4 axis may serve as a promising strategy for prevention of atherosclerotic diseases. We showed herein that miR-92 contributed to the development of atherosclerosis by directly controlling macrophage polarization. Inhibition of miR-92 downregulated markers that represent classical activated macrophages but increased alternative activated macrophages markers. Moreover, miR-92 inhibitor treated ApoE-/- mice fed with HFD leaded to alleviated atherosclerotic plaque size and increased stability characterizes. Mechanistically, miR-92 can directly target KLF4 which was required for the macrophage polarization mediated by miR-92 silencing. [Display omitted]