Bromodomain Blockade for Intimal Hyperplasia--A Good BET?
Bromodomain Blockade for Intimal Hyperplasia--A Good BET?
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DOI：
10.1016/j.ebiom.2015.11.007
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发表时间：
2015-11
期刊：
影响因子：
11.1
通讯作者：
Martin KA
中科院分区：
文献类型：
--
作者：
Ostriker AC;Martin KA
动脉粥样硬化导致心脏病发作、中风和外周血管疾病，并且仍然是美国的主要死亡原因（塔巴斯等人，2015年）。动脉粥样硬化斑块可以通过血管重建手术来治疗，包括血管成形术、支架植入术或旁路手术，但是在这些手术期间对血管的微创伤可以导致称为内膜增生的并发症，即血管腔中细胞的过度增殖（Katz等人，2015年）的报告。平滑肌细胞（SMC），其中包括动脉的肌肉层，保持显着的能力，去分化，以响应损伤，并承担修复表型。这些SMC下调其特征性收缩蛋白的表达，并从血管壁迁移到管腔中，在管腔中它们增殖并分泌基质蛋白，形成纤维化瘢痕（Liu et al.，2015年）的报告。虽然用药物洗脱支架进行局部药物递送在减少冠状动脉中的内膜增生方面是有效的，但内膜增生仍然是糖尿病患者和外周血管中的主要挑战（Katz等人，2015年）的报告。在本期中，Wang等提出了令人兴奋的发现，靶向表观遗传“阅读器”蛋白是预防内膜增生的一种有前途的治疗策略。我们对内膜增生反应背后的平滑肌表型转换的理解主要是在转录水平上，但最近的研究揭示了表观遗传调控的作用，包括DNA甲基化和将DNA组织成染色质的组蛋白的修饰。总的来说，这些表观遗传修饰由被称为“写入器”和“擦除器”的蛋白质进行，控制染色质对转录因子的可及性（Liu等人，2015）。阅读器蛋白的布罗莫结构域和末端外结构域（BET）家族充当关键衔接子，识别组蛋白乙酰化赖氨酸残基并募集额外的蛋白质以促进转录延伸（Shi和Vakoc，2014）。Wang等人证明BET蛋白在内膜增生中起重要作用。作者发现BET蛋白BRD4在正常大鼠颈动脉中以低水平表达，但在球囊血管成形术后的SMC中高度诱导。BRD4也存在于人静脉和动脉移植物内膜增生病变中，但不存在于正常血管中。最令人兴奋的发现是BET特异性布罗莫结构域抑制剂JQ1，
Atherosclerosis contributes to heart attack, stroke, and peripheral vascular disease and remains the leading cause of death in the US (Tabas et al., 2015). Atherosclerotic plaques can be treated by revascularization procedures, including angioplasty, stenting, or bypass surgery, but microtrauma to the blood vessel during these procedures can lead to a complication called intimal hyperplasia, a hyperproliferation of cells in the vascular lumen (Katz et al., 2015). Smooth muscle cells (SMC), which comprise the muscular layer of arteries, retain the remarkable ability to dedifferentiate in response to injury and assume a repair phenotype. These SMC downregulate expression of their characteristic contractile proteins and migrate from the vessel wall into the lumen where they proliferate and secrete matrix proteins, forming a fibrotic scar (Liu et al., 2015). While local drug delivery with drug-eluting stents has been effective in reducing intimal hyperplasia in coronary arteries, intimal hyperplasia remains a major challenge in diabetic patients and in peripheral blood vessels (Katz et al., 2015). In this issue, Wang et al. present exciting findings that targeting epigenetic “reader” proteins is a promising therapeutic strategy for preventing intimal hyperplasia.Our understanding of the smooth muscle phenotypic switching that underlies the intimal hyperplastic response has been largely at the transcriptional level, but recent studies revealed roles for epigenetic regulation, including DNA methylation and modifications of the histone proteins that organize DNA into chromatin. Collectively, these epigenetic modifications, made by proteins referred to as “writers” and “erasers”, govern chromatin accessibility to transcription factors (Liu et al. 2015). The bromodomain and extraterminal domain (BET) family of reader proteins serve as critical adaptors, recognizing histone acetylated lysine residues and recruiting additional proteins to promote transcription elongation (Shi and Vakoc, 2014). Wang et al. demonstrate that BET proteins play an important role in intimal hyperplasia. The authors found that the BET protein BRD4 was expressed at low levels in normal rat carotid artery but was highly induced in SMC following balloon angioplasty. BRD4 was also present in human vein and artery graft intimal hyperplastic lesions but not in normal vessels. The most exciting finding was that a BET-specific bromodomain inhibitor, JQ1, reduced intimal