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

Abstract

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.

• Authors: Hai-Peng Cheng, Duo Gong, Zhen-Wang Zhao, Ping-Ping He, Xiao-Hua Yu, Qiong Ye, Chong Huang, Xin Zhang, Ling-Yan Chen, Wei Xie, Min Zhang, Liang Li, Xiao-Dan Xia, Xin-Ping Ouyang, Yu-Lin Tan, Zong-Bao Wang, Guo-Ping Tian, Xi-Long Zheng, Wei-Dong Yin, Chao-Ke Tang
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 82 Issue 1 Pg. 28-38 (12 25 2017) ISSN: 1347-4820 [Electronic] Japan
• PMID: 28855441 (Publication Type: Journal Article)

Chemical References

• Cytokines
• MicroRNAs
• Mirn182 microRNA, human
• Mirn182 microRNA, mouse
• Repressor Proteins
• Lipoprotein Lipase
• Hdac9 protein, mouse
• Histone Deacetylases

Topics

• Animals
• Atherosclerosis (chemically induced)
• Computational Biology
• Cytokines (drug effects)
• HEK293 Cells
• Histone Deacetylases
• Humans
• Inflammation (metabolism)
• Lipid Metabolism (drug effects)
• Lipoprotein Lipase (drug effects)
• Macrophages
• Mice
• Mice, Knockout, ApoE
• MicroRNAs (pharmacology)
• Repressor Proteins (antagonists & inhibitors)
• THP-1 Cells