{Reference Type}: Journal Article
{Title}: Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4.
{Author}: Zhai K;Deng L;Wu Y;Li H;Zhou J;Shi Y;Jia J;Wang W;Nian S;Jilany Khan G;El-Seedi HR;Duan H;Li L;Wei Z;
{Journal}: J Adv Res
{Volume}: 0
{Issue}: 0
{Year}: 2024 Aug 8
{Factor}: 12.822
{DOI}: 10.1016/j.jare.2024.08.012
{Abstract}: <B>BACKGROUND: </B>Exosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated.<BR><B>OBJECTIVE: </B>To explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS.<BR><B>METHODS: </B>We isolated and identified exosomes from THP-1 macrophages after treating them with ox-LDL. Then used co-immunoprecipitation and silver staining to identify the proteins involved in regulating exosome release. PKH67 was used to label exosomes to confirm that cells can absorb them, and then co-culture with HVSMCs for cell proliferation and migration detection. The target genes of miR-146a were screened and identified through bioinformatics and luciferase activity assay, and the expression of miR-146a and related proteins was detected through qRT-PCR and Western blot in HUVECs. An AS model in LDLR-/- mice induced by a high-fat diet was developed to investigate the impact of exosome-miR-146a on AS.<BR><B>RESULTS: </B>The results showed that experimental foam cells from AS showed higher expression of miR-146a. It was observed that NMMHC IIA and HSP70 interacted to regulate the release of exosomes. And HUVECs can absorb exosomes derived from macrophages. In addition, we also found that miR-146a directly targeted the SMAD4 gene to modulate the p38 MAPK signaling pathway, thereby mediating HUVECs damage. Furthermore, exosome-miR-146a induced abnormal proliferation and migration of HVSMCs. The expression of miR-146a was significantly reduced in miR-146a-mimics mice and increased in miR-146a inhibitor mice whereas the inhibition of miR-146a effectively reduced while increasing miR-146a worsened AS in mice.<BR><B>CONCLUSIONS: </B>Our findings expressed the potential of miR-146a as a favorable therapeutic target for AS, however, further exploration is suggestive for deep understanding of the mechanisms regulating exosome-miR-146a release in vivo and to develop effective therapeutic strategies involving miR-146a.