Abstract 19359: Inhibition of miR-146a Attenuates Neointima Formation
Introduction: Drug-eluting stents are used to prevent in-stent-restenosis. However, anti-proliferative agents delivered lack cell specificity and also impair reendothelialization. Micro RNAs are promising therapeutical targets as they exhibit diverse and distinct cell specific functions and can be effectively attacked in vivo.
Hypothesis: Here, we propose miR-146a as a putative target beneficial for the treatment of noontima formation following vascular injury.
Methods and Results: Micoarray analysis revealed a significant upregulation of miR-146a upon wire-induced injury in C57BL6/N mice. The inhibition of miR-146a in vitro led to opposing effects in endothelial (EC) and vascular smooth muscle cells (VSMC). EC proliferation and migration was induced, whereas VSMC proliferation and migration were reduced significantly. Vasorin, a transmembrane protein, mainly expressed in VSMC, was verified as a direct target mRNA of miR-146a as shown by qRT-PCR, Western Blot analysis and luciferase assays. Continually, vasorin mRNA was shown to be downregulated upon wire-induced injury in vivo. In a subsequent in vivo study, a miR-146a inhibitor was applied locally in a self-degrading pluronic gel after wire-induced injury. Ablation of miR-146a led to the reduction of neointimal hyperplasia in mice 21 days after injury (Neointima/Media Ratio 2.84 in control vs 1.72 in treated animals p<0.01). In this context also VSMC proliferation was reduced significantly as assessed by Ki67 immunofluorescence. In contrast, re-endothelialization was significantly improved compared to control animals as assessed by Evan’s Blue incorporation.
Conclusions: This study reports an essential role of miR-146a during vascular remodeling. Inhibition of miR-146a is sufficient to improve the outcome upon wire-induced injury by preventing SMC proliferation while supporting EC regeneration. Thus, miR-146a represents a novel promising target to treat and prevent post-angioplasty restenosis.
Author Disclosures: D. Sedding: None. L. Korte: None. R. Teske: None. K. Donde: None. J. Bauersachs: None.
- © 2016 by American Heart Association, Inc.