Abstract 232: E-selectin-targeting Microparticle-mediated Delivery of MicroRNAs for the Treatment of Atherosclerosis
Rationale: E-selectin on inflamed endothelium promotes atherosclerosis and also provides binding sites for targeted drug delivery. We identified an E-selectin-targeting thioaptamer (ESTA) and conjugated it onto a multistage vector (MSV) to form an ESTA-MSV microparticle. In this study, we tested targeted delivery of therapeutic microRNAs (miRs) loaded in the ESTA-MSV for the treatment of atherosclerosis.
Methods and Results: The expression of E-selectin was up-regulated, while the expressions of miR-146a and miR-181b were down-regulated, in TNF-α-treated human microvascular endothelial cells (HMVECs). MiR-146a and miR-181b mimics were packaged into ESTA-MSV microparticles. We found that both the miR-146a and miR-181b significantly attenuated TNF-α-induced up-regulation of adhesion molecules. Moreover, the monocyte adhesion to HMVECs was also attenuated by the miR-146a or miR-181b. The ApoE-/- mice were injected with ESTA-MSV-packaged miR-146a or miR-181b mimic biweekly through tail vein for 12 weeks. Injection of miR mimics resulted in a 4.7- and 5.7-fold overexpression of miR-146a and miR-181b in mouse aortas. The immunofluorescence staining showed the co-localization of E-selectin and miRs in aortic endothelium. MiR-146a and miR-181b significantly inhibited atherosclerotic lesion size, lipids deposition, macrophage and lymphocyte infiltration in plaques, and gene expression of adhesion molecules in aortas.
Conclusions: E-selectin-targeting delivery of miR-146a and miR-181b inhibits atherosclerosis. These findings provide a novel delivery system for miR-based therapy of atherosclerosis.
Author Disclosures: S. Ma: None. X. Tian: None. C. Mu: None. H. Shen: None. J. Bismuth: None. W. Wong: None.
- © 2015 by American Heart Association, Inc.