MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.
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ABSTRACT: Abdominal aortic aneurysm (AAA) is a serious vascular disease featured by inflammatory infiltration in aortic wall, aortic dilatation and extracellular matrix (ECM) degradation. Dysregulation of microRNAs (miRNAs) is implicated in AAA progress. By profiling miRNA expression in mouse AAA tissues and control aortas, we noted that miR-126a-5p was down-regulated by 18-fold in AAA samples, which was further validated with real-time qPCR. This study was performed to investigate miR-126a-5p's role in AAA formation. In vivo, a 28-d infusion of 1 ?g/kg/min Angiotensin (Ang) II was used to induce AAA formation in Apoe-/- mice. MiR-126a-5p (20 mg/kg; MIMAT0000137) or negative control (NC) agomirs were intravenously injected to mice on days 0, 7, 14 and 21 post-Ang II infusion. Our data showed that miR-126a-5p overexpression significantly improved the survival and reduced aortic dilatation in Ang II-infused mice. Elastic fragment and ECM degradation induced by Ang II were also ameliorated by miR-126a-5p. A strong up-regulation of ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS-4), a secreted proteinase that regulates matrix degradation, was observed in smooth muscle cells (SMCs) of aortic tunica media, which was inhibited by miR-126a-5p. Dual-luciferase results demonstrated ADAMTS-4 as a new and valid target for miR-126a-5p. In vitro, human aortic SMCs (hASMCs) were stimulated by Ang II. Gain- and loss-of-function experiments further confirmed that miR-126-5p prevented Ang II-induced ECM degradation, and reduced ADAMTS-4 expression in hASMCs. In summary, our work demonstrates that miR-126a-5p limits experimental AAA formation and reduces ADAMTS-4 expression in abdominal aortas.
SUBMITTER: Li L
PROVIDER: S-EPMC7348185 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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