Journal of cardiology · 2021
Inhibition of MicroRNA-92 alleviates atherogenesis by regulation of macrophage polarization through targeting KLF4.
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Gao Feng, Chen Xueying, Xu Banglong, Luo Zhidan, Liang Yi, Fang Sihua, Li Mengli, Wang Xiaochen, Lin Xianhe
Аннотация
BACKGROUND: 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.
METHODS AND RESULTS: 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.
CONCLUSION: 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.
METHODS AND RESULTS: 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.
CONCLUSION: 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.