【論文摘要】Senescence Related Endothelial Progenitor Cell Dysfunction through microRNA-409 and CCL5 Signaling

Yen-Hung Chou ； Yih-Jer Wu ； Yi-Nan Lee ； Hung-I Yeh ； Cheng-Huang Su ； Anne Chen ； Hsin-I Lee ； Chiung-Yin Chang

《海峽循環醫學雜誌》 1卷2S期 (2019/09) Pp. 148-148

https://doi.org/10.6907/SCJ.201909/SP_1(2).0121

摘要

Background/Synopsis: Cumulative evidences show that endothelial progenitors cells (EPCs) play a crucial role in neoangiogenesis and vascular repair. Senescence related EPC dysfunction contributes to aging-induced atherosclerosis and organ ischemia. Chemokine receptor-5 (CCR5)/chemokine ligan-5 (CCL5) signaling has recently been shown to facilitate EPC recruitment and the stabilization of atherosclerotic plaques. The role of CCL5 in EPC senescence is unclear. Objectives/Purpose: We sought to investigate whether senescence induced EPC dysfunction is mediated by CCR5/CCL5 pathway and whether microRNAs (miRs) play a role on this process. Methods/Results: EPCs were isolated from peripheral blood of healthy donors. CCL5 paracrine levels from replication-induced senescent EPCs were significantly reduced (P＜0.05) as compared with those from their younger counterparts. In line with this observation, CCL5 paracrine levels were demonstrated inversely correlated with age (n=132, r=-0.42, p＜0.01) and Framingham Risk Score (r=-0.48, p＜0.01) but positively associated with vascular endothelial growth factor (VEGF) paracrine levels (r=0.53, p＜0.001). We found that CCL5 was able to increase its cognate receptor CCR5 in a positive-feedback mode, and moreover, to enhance EPC proliferation through PI3K/Akt/mTOR/p70s6k pathway. miR-409, which was significantly upregulated in senescent EPC from our miR array analysis, was found to significantly inhibit EPC proliferation and migration. Intriguingly, miR-409 was also shown to significantly inhibit CCL5 paracrine levels, as well as CCL5 and CCR5 mRNA expression. On the other hand, miR-409 significantly decreases p70s6k levels. In addition, we confirmed that miR-409 abolished CCL5 enhanced EPC proliferation through p70s6k pathway. Conclusion: CCL5 significantly attenuates senescence-induced EPC dysfunction which may be mediated through upregulation of miR-409-3p along with EPC senescence. CCL5 may provide a promising therapeutic potential to ameliorate senescence-induced EPC dysfunction and slow down the progress of aging-induced vascular diseases.