Abstract P3044: MicroRNA-127-3p Regulates Inflammatory Response In Injury-induced Vascular Remodeling And Cellular Senescence In Vascular Smooth Muscle Cells

Abstract

The accumulation of senescent cells in the vasculature over the lifespan contributes to vascular remodeling due to the severely impaired functional properties of the cells. MicroRNAs (miRs) are promising therapeutical targets as they exhibit diverse and cell-specific functions and can be effectively targeted in vivo . Here, we propose that targeting miR-127-3p might be an attractive approach to enhance vascular healing and regeneration in a cell-specific manner, thereby limiting angioplasty-related complications. The initial screenings revealed miR-127-3p as a highly regulated miR in the process of restenosis 7 and 21 days (p<0.001) after wire induced-injury and in aged (20 months) C57BL/6 mice (p<0.05) in vivo . Additionally, replicative senescent vascular smooth muscle cells (SMC) and human coronary artery endothelial cells (EC) showed an enhanced expression of miR-127-3p (p<0.05) compared to non-senescent cells. Functional effects of miR-127-3p on SMCs and ECs were assessed via transfection with either pre-miR or antagomir. Overexpression of miR-127-3p in vitro reduced SMC proliferation (p<0.05) and altered migrational capacity. Downregulation of miR-127-3p resulted in a reverse effect. In contrast, cellular functions were not altered in ECs. We further identified potential targets with effects on inflammation and cellular aging by in silico analysis and verified them on mRNA and protein levels by qRT-PCR and western blot analysis. As a direct target of miR-127-3p, the senescence-associated gene CD44 was identified by TargetScan. Expression of CD44 was altered on mRNA and protein levels after overexpression respectively downregulation of miR-127-3p in SMCs. Further, p14arf and laminB1 were downregulated after overexpression of miR-127-3p in SMCs, contrary to the effect after downregulation of miR-127-3p with increased mRNA levels of p14arf and laminB1. In this study, we identified miR-127-3p as a contributing factor in SMC function during the development of cellular senescence and show that it might therewith also be a modulating factor in the process of restenosis. However, further studies need to be carried out to validate the potential of miR-127-3p as a therapeutic target in vascular aging and remodeling in vitro and in vivo .