Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia.
Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia.
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DOI：
10.1016/j.atherosclerosis.2020.06.002
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发表时间：
2020-09
期刊：
影响因子：
5.3
通讯作者：
Guo LW
中科院分区：
文献类型：
--
作者：
Huang Y;Urabe G;Zhang M;Li J;Ozer HG;Wang B;Kent KC;Guo LW
组蛋白甲基转移酶是表观遗传学治疗的新兴靶点。DOT 1 L（disruptor of telomeric silencing 1-like）是唯一已知的组蛋白3赖氨酸79（H3 K79）的甲基化书写者。对心血管疾病的干预研究较少。我们研究了DOT 1 L在新生内膜增生（IH）中的作用，这是闭塞性血管疾病的基本病因。通过球囊血管成形术在大鼠颈动脉中诱导IH。DOT 1 L及其催化产物H3 K79 me 2和H3 K79 me 3（免疫染色）在损伤后第7天的颈动脉中分别增加了4.69 ±0.34、2.38 ±0.052和3.07 ±0.27倍。在第14天，通过shRNA-慢病毒输注损伤动脉中的DOT 1 L沉默使DOT 1 L、H3 K79 me 2和IH分别降低了54.5%、37.1%和76.5%。此外，血管周围施用DOT 1 L选择性抑制剂（EPZ 5676）分别使H3 K79 me 2、H3 K79 me 3和IH减少56.1%、58.6%和39.9%。此外，DOT 1 L沉默及其在体内损伤动脉中的抑制（与EPZ 5676一起）增强了平滑肌α-肌动蛋白免疫染色;用EPZ 5676体外预处理平滑肌细胞减少了促增殖标志物蛋白，包括增殖细胞核抗原（PCNA）和细胞周期蛋白-D1。虽然DOT 1 L在血管成形术损伤的大鼠颈动脉中上调，但其遗传沉默或药理学抑制减少了损伤诱导的IH。因此，这项研究提出了一个强有力的理由，扩大机制和翻译研究DOT 1 L靶向治疗（再）狭窄血管疾病。
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 for occlusive vascular diseases. 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. 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 extending mechanistic and translational investigation into DOT1L targeting for treatment of (re)stenotic vascular conditions.
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