MicroRNA-182 Promotes Lipoprotein Lipase Expression and Atherogenesisby Targeting Histone Deacetylase 9 in Apolipoprotein E-Knockout Mice

• Published in: Circulation Journal 2017/12/25, Vol.82(1), pp.28-38
• Main Authors: Cheng, Hai-Peng, Gong, Duo, Zhao, Zhen-Wang, He, Ping-Ping, Yu, Xiao-Hua, Ye, Qiong, Huang, Chong, Zhang, Xin, Chen, Ling-Yan, Xie, Wei, Zhang, Min, Li, Liang, Xia, Xiao-Dan, Ouyang, Xin-Ping, Tan, Yu-Lin, Wang, Zong-bao, Tian, Guo-Ping, Zheng, Xi-Long, Yin, Wei-Dong, Tang, Chao-Ke
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis; Atherosclerosis - chemically induced; Computational Biology; Cytokines - drug effects; HEK293 Cells; Histone deacetylase 9 (HDAC9); Histone Deacetylases; Humans; Inflammation; Inflammation - metabolism; Lipid Metabolism - drug effects; Lipoprotein lipase (LPL); Lipoprotein Lipase - drug effects; Macrophages; Mice; Mice, Knockout, ApoE; MicroRNA-182; MicroRNAs - pharmacology; Repressor Proteins - antagonists & inhibitors; THP-1 Cells
• ISSN: 1346-9843; 1347-4820; 1347-4820
• DOI: 10.1253/circj.CJ-16-1165

Background:Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson’s trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice.Conclusions:The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.