Abstract 631: Neointima Abating Yet Endothelium Preserving-An Adventitia-localized Nanoformulation To Inhibit The Epigenetic Writer Dot1L

Abstract

Open vascular reconstructions such as bypass are common treatments for cardiovascular disease. Unfortunately, neointimal hyperplasia (IH) follows, leading to treatment failure for which there is no approved therapy. Here we combined the strengths of tailoring nanoplatforms for open vascular reconstructions and targeting new epigenetic mechanisms. We produced adhesive nanoparticles (ahNP) that could be pen-brushed and immobilized on the adventitia to sustainably release pinometostat, an inhibitor drug selective to the epigenetic writer DOT1L that catalyzes histone-3 lysine-79 dimethylation (H3K79me2). This treatment not only reduced IH by 66.3% in injured arteries (mimicking open reconstructions) in obese Zucker rats with human-like diseases, but also avoided endothelial impairment-a shortcoming in current IH managements. In mechanistic studies, chromatin immunoprecipitation (ChIP) sequencing revealed co-enrichment of the histone code H3K27ac(acetyl) and its reader BRD4 at the gene of aurora kinase B (AURKB), where H3K79me2 was also enriched as indicated by ChIP-qPCR. Accordingly, DOT1L co-immunoprecipitated with H3K27ac. Furthermore, the known IH driver BRD4 governed the expression of DOT1L which controlled AURKB’s protein level, revealing a BRD4->DOT1L->AURKB axis. Consistently, AURKB-selective inhibition also reduced IH. Thus, this study presents a prototype nanoformulation suited for open vascular reconstructions, and the new insights into epigenetic regulators may aid future translational advances.