| First Author | Shi X | Year | 2020 |
| Journal | J Mol Cell Cardiol | Volume | 143 |
| Pages | 1-14 | PubMed ID | 32278833 |
| Mgi Jnum | J:296919 | Mgi Id | MGI:6441567 |
| Doi | 10.1016/j.yjmcc.2020.04.008 | Citation | Shi X, et al. (2020) MiR-144-5p limits experimental abdominal aortic aneurysm formation by mitigating M1 macrophage-associated inflammation: Suppression of TLR2 and OLR1. J Mol Cell Cardiol 143:1-14 |
| abstractText | BACKGROUND: It has been noted that dysregulation of microRNAs (miRNAs) contributes to the formation of abdominal aortic aneurysm (AAA), a vascular disease associated with progressive aortic dilatation and degradation, and pathological infiltration and activation of inflammatory cells, such as macrophages. Our microarray data revealing that miR-144-5p was the top 1 downregulated miRNA in mouse AAA tissues as compared to normal aortas motivated us to explore its role in AAA development. METHODS: We profiled miRNA and mRNA expression in Angiotensin II (Ang II)- (n=3) and saline-infused abdominal aortas (n=4) via Agilent microarrays, and further validated the data with real-time QPCR. In vivo, miR-144-5p or control agomirs were given to Apoe(-/-) mice with Ang II infusion-induced AAA. In vitro, mouse RAW 264.7 macrophages and human THP-1 macrophage-like cells were transfected with miR-144-5p or control agomirs/antagomirs, and oxidized Low Density Lipoprotein (ox-LDL) was used to stimulate M1 macrophage polarization. RESULTS: Based on the microarray and real-time QPCR validation data, we identified miR-144-5p as a novel downregulated miRNA in AAA tissues. Overexpression of miR-144-5p by utilizing its specific agomirs in vivo significantly attenuated Ang II-induced aortic dilatation and elastic degradation in Apoe(-/-) mice and improved their survival. AAA incidence was reduced by miR-144-5p as well. MiR-144-5p polarized macrophages to M2 type in Ang II-infused aortas. Further, the expression levels of two predictive targets for miR-144-5p, Toll Like Receptor 2 (TLR2) and ox-LDL Receptor 1 (OLR1), were higher in AAA specimens, and negatively correlated to miR-144-5p (Pearson correlation coefficient r<-0.9, P<.01). These two molecules were then confirmed as novel miR-144-5p targets via dual-luciferase assay. MiR-144-5p agomirs suppressed ox-LDL-induced upregulation of M1 macrophage markers, including interleukin 1beta (IL1beta), tumor necrosis factor alpha (TNFalpha), prostaglandin-endoperoxide synthase 2 (PTGS2) and nitric oxide synthase 2 (NOS2), in macrophages probably by targeting TLR2. MiR-144-5p also inhibited the signaling transduction of pathways downstream to TLR2 and OLR1, including NF-kappaB and ERK1/2 pathways, whose abnormal activation contributed AAA formation. CONCLUSION: Our work suggests miR-144-5p as a novel regulator for AAA pathology. Management of miR-144-5p and its targets TLR2 and OLR1 provides therapeutic potential for limiting AAA formation. |
