Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia. (September 2020)

• Record Type: Journal Article
• Authors: Huang, Yitao; Urabe, Go; Zhang, Mengxue; Li, Jing; Ozer, Hatice Gulcin; Wang, Bowen; Kent, K. Craig; Guo, Lian-Wang
• Is Part Of: Atherosclerosis. Volume 308(2020)
• Page Start: 22
• Page End: 31
• Publication Date: 2020-09
• Subjects: DOT1L -- H3K79 methylation -- Epigenetic target -- In vivo silencing -- Neointimal hyperplasia; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2020.06.002
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Histone methyltransferases are emerging targets for epigenetic therapy. DOT1L (disruptor of telomeric silencing 1-like) is the only known methylation writer at histone 3 lysine 79 (H3K79). It is little explored for intervention of cardiovascular disease. We investigated the role of DOT1L in neointimal hyperplasia (IH), a basic etiology of occlusive vascular diseases. Methods and results: IH was induced via balloon angioplasty in rat carotid arteries. DOT1L and its catalytic products H3K79me2 and H3K79me3 (immunostaining) increased by 4.69 ± 0.34, 2.38 ± 0.052, and 3.07 ± 0.27 fold, respectively, in injured ( versus uninjured) carotid arteries at post-injury day 7. Dot1l silencing via shRNA-lentivirus infusion in injured arteries reduced DOT1L, H3K79me2, and IH at day 14 by 54.5%, 37.1%, and 76.5%, respectively. Moreover, perivascular administration of a DOT1L-selective inhibitor (EPZ5676) reduced H3K79me2, H3K79me3, and IH by 56.1%, 58.6%, and 39.9%, respectively. In addition, Dot1l silencing and its inhibition (with EPZ5676) in vivo in injured arteries boosted smooth muscle α-actin immunostaining; pretreatment of smooth muscle cells 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-injured rat carotid arteries, either its genetic silencing or pharmacological inhibition diminishes injury-induced IH. As such, this study presents a strong rationale for continued mechanistic and translational investigation into DOT1L targeting for treatment of (re)stenotic vascular conditions. Graphical abstract: Image 1 Highlights: DOT1L and its catalytic products H3K79me2 and H3K79me3 increased due to injury in rat carotid arteries after angioplasty. Silencing DOT1L in vivo inhibited H3K79 methylation and diminished injury-induced intimal hyperplasia. Treatment with a DOT1L inhibitor reduced H3K79 methylation and intimal hyperplasia.