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

Abstract

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.

Involvement of Myeloid Cells and Noncoding RNA in Abdominal Aortic Aneurysm Disease

“…In contrast, miR-181a seems to suppress inflammation by decreasing proinflammatory gene expression (e.g., VCAM-1, ICAM-1, and E-selectin) and infiltration of macrophages, leukocytes, and T cells into atherosclerotic plaques (127). Again, no direct association with AAA disease was shown so far.…”

“…Contributions from miRNAs to inflammatory processes have been demonstrated for a multitude of diseases (123), including rheumatoid arthritis (126), psoriasis (124), asthma (78), ulcerative colitis (147), systemic lupus erythematosus (133), different forms of glomerulonephritis (93), and also atherosclerosis (51,127).…”

Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

“…There is growing evidence that miRNAs control these pathologic processes including endothelial dysfunction (miR let-7g, mir-17-3p, miR-31, miR-146a, miR-155, miR-181 family, miR-221/-222,) [170][171][172][173][174][175], oxidative stress (miR-let-7a/b, miR-19b, miR-20a, miR-98, miR-126, miR-142-3p, miR-199a-3p and -5p, miR-200c, miR-221, miR-222, miR-328) [176][177][178][179][180][181][182][183][184][185][186][187][188][189], monocyte recruitment, differentiation and activation (miR-21, miR-23a-5p, miR-27a/b, miR-33, miR-34, miR-146a, miR-155, miR-212, miR-451, miR-590, miR-758-5p, [190][191][192][193][194][195][196][197][198][199][200][201] and inflammation/secretion of inflammatory cytokines (miR let-7g, miR-17-3p, miR-31, miR-146a, miR-155, miR-181a-3p/-5p, miR-181b, miR-221 and miR-222) [171,202,203]. Interestingly, a number of them are simultaneously involved in all those processes, suggesting common and/or cooperative activities, and underlying their relevance in the physiopathology of CVD.…”

MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

“…Systemic miR-181b delivery reduces NFkB activity and atherosclerotic lesion formation in Apoe −/− mice [47]. miR-181a-5p and miR-181a-3p inhibit vascular inflammation through regulation of the NFkB signalling pathway to inhibit VCAM-1, ICAM-1 and E-selectin expression [48]. Rescue of miR-181a-5p and miR-181a-3p significantly suppresses atherosclerotic plaque formation in Apoe −/− mice [48].…”

“…miR-181a-5p and miR-181a-3p inhibit vascular inflammation through regulation of the NFkB signalling pathway to inhibit VCAM-1, ICAM-1 and E-selectin expression [48]. Rescue of miR-181a-5p and miR-181a-3p significantly suppresses atherosclerotic plaque formation in Apoe −/− mice [48]. miR-146a is involved in a negative feedback loop control of NFkB signalling [49], by targeting TRAF6, which inhibits downstream IκB kinase (IKK) phosphorylation and nuclear translocation [50] to suppress ICAM-1 expression and macrophage migration [51].…”