MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis

• Published in: Cell death & disease 2019-05, Vol.10 (5), p.365, Article 365
• Main Authors: Su, Yingxue, Yuan, Jiani, Zhang, Feiran, Lei, Qingqing, Zhang, Tingting, Li, Kai, Guo, Jiawei, Hong, Yu, Bu, Guolong, Lv, Xiaofei, Liang, Sijia, Ou, Jingsong, Zhou, Jiaguo, Luo, Bin, Shang, Jinyan
• Format: Article
• Language: English
• Subjects: 13/109; 13/21; 14/19; 14/34; 38/77; 38/90; 64/60; 692/699/75/593/2100; 82/1; 82/80; 96/44; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antagomirs - metabolism; Antibodies; Aorta; Aorta - metabolism; Aorta - pathology; Apolipoprotein E; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - pathology; Biochemistry; Biomedical and Life Sciences; Cardiovascular disease; Cell activation; Cell Biology; Cell Culture; Coronary artery; Coronary vessels; Diet, High-Fat; Endothelial cells; Endothelium; Gene expression; Gene Expression - drug effects; Heart diseases; Human Umbilical Vein Endothelial Cells; Humans; Hyperlipidemia; I-kappa B Kinase - chemistry; I-kappa B Kinase - metabolism; Immunology; Inflammation; Inflammation - metabolism; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Life Sciences; Lipid metabolism; Lymphocytes T; Macrophages; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - blood; MicroRNAs - metabolism; miRNA; Monocytes; NF-kappa B - metabolism; NF-κB protein; Post-transcription; Signal Transduction; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1599-9

MicroRNAs have emerged as important post-transcriptional regulators of gene expression and are involved in diverse diseases and cellular process. Decreased expression of miR-181a has been observed in the patients with coronary artery disease, but its function and mechanism in atherogenesis is not clear. This study was designed to determine the roles of miR-181a-5p, as well as its passenger strand, miR-181a-3p, in vascular inflammation and atherogenesis. We found that the levels of both miR-181a-5p and miR-181a-3p are decreased in the aorta plaque and plasma of apoE −/− mice in response to hyperlipidemia and in the plasma of patients with coronary artery disease. Rescue of miR-181a-5p and miR-181a-3p significantly retards atherosclerotic plaque formation in apoE −/− mice. MiR-181a-5p and miR-181a-3p have no effect on lipid metabolism but decrease proinflammatory gene expression and the infiltration of macrophage, leukocyte and T cell into the lesions. In addition, gain-of-function and loss-of-function experiments show that miR-181a-5p and miR-181a-3p inhibit adhesion molecule expression in HUVECs and monocytes-endothelial cell interaction. MiR-181a-5p and miR-181a-3p cooperatively receded endothelium inflammation compared with single miRNA strand. Mechanistically, miR-181a-5p and miR-181a-3p prevent endothelial cell activation through blockade of NF-κB signaling pathway by targeting TAB2 and NEMO, respectively. In conclusion, these findings suggest that miR-181a-5p and miR-181a-3p are both antiatherogenic miRNAs. MiR-181a-5p and miR-181a-3p mimetics retard atherosclerosis progression through blocking NF-κB activation and vascular inflammation by targeting TAB2 and NEMO, respectively. Therefore, restoration of miR-181a-5p and miR-181a-3p may represent a novel therapeutic approach to manage atherosclerosis.