Background aims: Histone methyltransferases are emerging targets for epigenetic therapy. DOT1L (disruptor of telomeric silencing 1-like) may be the only known methylation author at histone 3 lysine 79 (H3K79). It’s little explored for intervention of coronary disease. We investigated the function of DOT1L in neointimal hyperplasia (IH), a fundamental etiology of occlusive vascular illnesses.
Methods and results: IH was caused via balloon angioplasty in rat carotid arterial blood vessels. DOT1L and it is catalytic products H3K79me2 and H3K79me3 (immunostaining) elevated by 4.69 ?à .34, 2.38 ?à .052, and three.07 ?à .27 fold, correspondingly, in hurt (versus uninjured) carotid arterial blood vessels at publish-injuries day 7. Dot1l silencing via shRNA-lentivirus infusion in hurt arterial blood vessels reduced DOT1L, H3K79me2, and IH at day 14 by 54.5%, 37.1%, and 76.5%, correspondingly. Furthermore, perivascular administration of the DOT1L-selective inhibitor (EPZ5676) reduced H3K79me2, H3K79me3, and IH by 56.1%, 58.6%, and 39.9%, correspondingly. Additionally, Dot1l silencing and it is inhibition (with EPZ5676) in vivo in hurt arterial blood vessels boosted smooth muscle |á-actin immunostaining pretreatment of smooth muscle tissues with EPZ5676 in vitro reduced pro-proliferative marker proteins, including proliferating cell nuclear antigen (PCNA) and cyclin-D1.
Conclusions: While DOT1L is upregulated in angioplasty-hurt rat carotid arterial blood vessels, either its genetic silencing or medicinal inhibition diminishes injuries-caused IH. As a result, this research presents a powerful rationale for ongoing mechanistic and translational analysis into DOT1L targeting to treat (re)stenotic vascular conditions.