PMID- 33545131 OWN - NLM STAT- MEDLINE DCOM- 20210830 LR - 20211204 IS - 1090-2422 (Electronic) IS - 0014-4827 (Linking) VI - 400 IP - 1 DP - 2021 Mar 1 TI - MiR-375 silencing attenuates pro-inflammatory macrophage response and foam cell formation by targeting KLF4. PG - 112507 LID - S0014-4827(21)00038-0 [pii] LID - 10.1016/j.yexcr.2021.112507 [doi] AB - 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-375(-/-)ApoE(-/-) 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. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Qiu, Yanyan AU - Qiu Y AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Xu, Jinyi AU - Xu J AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. Electronic address: xu_jin_yi_hn@126.com. FAU - Yang, Lihong AU - Yang L AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Zhao, Guihua AU - Zhao G AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Ding, Jing AU - Ding J AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Chen, Qiong AU - Chen Q AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Zhang, Na AU - Zhang N AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Yang, Ruike AU - Yang R AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Wang, Jijing AU - Wang J AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Li, Shuaibing AU - Li S AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. FAU - Zhang, Luming AU - Zhang L AD - Department of Cardio-Pulmonary Function, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210203 PL - United States TA - Exp Cell Res JT - Experimental cell research JID - 0373226 RN - 0 (Klf4 protein, mouse) RN - 0 (Kruppel-Like Factor 4) RN - 0 (Kruppel-Like Transcription Factors) RN - 0 (MicroRNAs) RN - 0 (Mirn375 microRNA, mouse) SB - IM MH - Animals MH - Atherosclerosis/etiology/metabolism/pathology/*prevention & control MH - Female MH - Inflammation/etiology/metabolism/pathology/*prevention & control MH - Kruppel-Like Factor 4 MH - Kruppel-Like Transcription Factors/*antagonists & inhibitors MH - *Macrophage Activation MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Knockout, ApoE MH - MicroRNAs/*antagonists & inhibitors/genetics MH - Signal Transduction OTO - NOTNLM OT - Foam cell OT - Inflammation OT - KLF4 OT - Macrophage OT - miR-375 EDAT- 2021/02/06 06:00 MHDA- 2021/08/31 06:00 CRDT- 2021/02/05 20:09 PHST- 2020/10/12 00:00 [received] PHST- 2021/01/18 00:00 [revised] PHST- 2021/01/26 00:00 [accepted] PHST- 2021/02/06 06:00 [pubmed] PHST- 2021/08/31 06:00 [medline] PHST- 2021/02/05 20:09 [entrez] AID - S0014-4827(21)00038-0 [pii] AID - 10.1016/j.yexcr.2021.112507 [doi] PST - ppublish SO - Exp Cell Res. 2021 Mar 1;400(1):112507. doi: 10.1016/j.yexcr.2021.112507. Epub 2021 Feb 3.