Upregulation of miR-301a promotes aneurysm progression by inducing macrophage M1 polarization through the PTEN/PI3K/AKT signaling axis
Objective:To investigate the mechanism by which miR-301a accelerates the progression of angiotensin Ⅱ(An-gⅡ)-induced abdominal arterial aneurysm(AAA)by regulating macrophage M1 polarization through the PTEN/PI3K/AKT sig-naling pathway.Methods:In in vivo experiments,8-10-week-old ApoE-/-male mice were divided into control,model,and miR-301a overexpression groups,and saline(saline)infusion was used as the control group(n=15),and the AAA model was built up by angiotensin Ⅱ(AngⅡ)induction(n=45);THP-1 cells were randomly divided into the control group,AngⅡ+agomir NC group,AngⅡ+miR-301a agomir group and AngⅡ+miR-301a agomir+LY(LY294002)group;the mechanism of miR-301a regulating macrophage polarization for aneurysm progression was elucidated by using bioinformatics,ELISA,West-ern blot,qRT-PCR,and dual luciferase reporter assay.Results:miR-301a expression was upregulated in the AAA group com-pared with the control,and all AngⅡ-injected mice exhibited larger aortic diameters.targetScan7.2 database predicted the exis-tence of a binding site between miR-301a and PTEN,and dual-luciferase reporter gene analysis confirmed that miR-301a directly targeted the PTEN gene.GO and KEGG pathway analysis revealed that the pathway of PI3K/AKT/and NF-κB signaling may be a key pathway for macrophage polarization toward M1.In vivo and in vitro experiments demonstrated that miR-301a regulated macrophage polarization toward the M1 phenotype through inhibition of PTEN and activation of the PI3K/AKT signaling pathway upregulated the expression of matrix metalloproteinases and inflammatory factors,and promoted aneurysm progression.In addi-tion,plasma miR-301a in combination with MMP-9's could be a candidate biomarker for predicting aneurysm rupture.Conclu-sions:miR-301a plays a key role in disease progression in AAA by promoting M1 polarization of macrophages via the PTEN/PI3K/AKT pathway,thereby accelerating aneurysm progression.
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