Mouse bone marrow derived mesenchymal stem cells-secreted exosomal microRNA-125b-5p suppresses atherosclerotic plaque formation via inhibiting Map4k4.

BACKGROUND:Accumulating evidence has reported the role of microRNA (miR) on atherosclerosis (AS), while it is unclear about the relationship between microRNA-125b-5p (miR-125b-5p) and AS. Thus, the object of this study was to investigate the impact of exosomal miR-125b-5p targeting mitogen-activated protein 4 kinase 4 (Map4k4) on AS plaque formation. METHODS:The AS model was established using a high fat diet in ApoE^-/- mice. Mouse bone marrow-derived mesenchymal stem cells (BMSCs) were selected and BMSC-exosomes (BMSC-EXO) were extracted and then identified. The targeted relationship between miR-125b-5p and Map4k4 was tested. BMSC-EXO were modified with miR-125b-5p- and Map4k4-related sequences to interfere with AS mice. MiR-125b-5p and Map4k4 expression in AS tissues were tested. The inflammation-related indices, blood lipid, plaque area, apoptosis index, MMP-9 and α-SMA expression in mice with AS were measured. RESULTS:BMSCs and BMSC-EXO were successfully isolated. MiR-125b-5p was down-regulated and Map4k4 was up-regulated in aorta tissues from ApoE^-/- mice after AS modeling, verses those from C57BL/6 mice without modeling. MiR-125b-5p targeted Map4k4. BMSC-EXO increased miR-125b-5p expression and decreased Map4k4 expression. BMSC-EXO/up-regulated miR-125b-5p and down-regulated Map4k4 in exosomes decreased inflammatory reaction, blood lipid, plaque area, MMP-9 expression and increased α-SMA expression, as well as inhibited apoptosis index of AS mice. CONCLUSION:Functional studies revealed that exosomal miR-125b-5p from BMSCs suppresses atherosclerotic plaque formation via inhibiting Map4k4 expression. Copyright © 2021 Elsevier Inc. All rights reserved.

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