Mesenchymal stem cell-derived extracellular vesicles relieve endothelial cell senescence via recovering CTRP9 upon repressing miR-674-5p in atherosclerosis.

BACKGROUND

The senescence of endothelial cells is of great importance involving in atherosclerosis (AS) development. Recent studies have proved the protective role of mesenchymal stem cell-derived extracellular vesicles in AS, herein, we further desired to unvei their potential regulatory mechanisms in endothelial cell senescence.

METHODS

Senescence induced by HO in primary mouse aortic endothelial cells (MAECs) was evaluated by SA-β-gal staining. Targeted molecule expression was detected by qRT-PCR and Western blotting. The biological functions of MAECs were determined by CCK-8, flow cytometry, transwell, and tube formation assays. Oxidative injury was assessed by LDH, total and lipid ROS, LPO and MDA levels. The proliferation of adipose-derived mesenchymal stem cell (ADSCs) was analyzed by EdU assay. Effect of ADSCs-derived extracellular vesicles (ADSC-EVs) on AS was investigated in HFD-fed mice.

RESULTS

miR-674-5p was up-regulated, while C1q/TNF-related protein 9 (CTRP9) was down-regulated in HO-induced senescent MAECs. CTRP9 was demonstrated as a target gene of miR-674-5p. miR-674-5p inhibition restrained senescence, oxidative stress, promoted proliferation, migration, and angiogenesis of HO-stimulated MAECs via enhancing CTRP9 expression. Moreover, treatment with ADSC-EVs inhibited HO-induced senescence and dysfunction of MAECs through regulating miR-674-5p/CTRP9 axis. In the AS mouse model, ADSC-EVs combination with miR-674-5p silencing slowed down AS progression via up-regulation of CTRP9.

CONCLUSION

ADSC-EVs repressed endothelial cell senescence and improved dysfunction via promotion of CTRP9 expression upon miR-674-5p deficiency during AS progression, which might provide vital evidence for ADSC-EVs as a promising therapy for AS.