The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation
The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation
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DOI：
10.1016/j.cellsig.2019.05.005
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发表时间：
2019-09-01
影响因子：
4.8
通讯作者：
Guo, Lian-Wang
中科院分区：
文献类型：
--
作者：
Zhang, Mengxue;Wang, Bowen;Guo, Lian-Wang
背景资料：静脉-移植物旁路术通常用于克服动脉粥样硬化，但主要由于新生内膜壁增厚而受到高失败率的限制。最近的研究表明，内皮-间质转化（EndoMT）是静脉移植物新生内膜形成的关键。BET是一个含有Bromo/ExtraTerminal结构域的表观遗传阅读器蛋白家族（BRD 2、BRD 3、BRD 4）。它们通过其独特的串联溴结构域（BD 1，BD 2）结合乙酰化组蛋白，促进转录复合物形成和细胞状态转换。BET的作用，包括个别BRD和他们独特的BD，是不是很好地理解在EndoMT和neointimal formation.Methods和结果：BRD 4表达的抑制废除TGF β 1诱导的EndoMT，具有更大的影响比BRD 2或BRD 3敲低。在所有BET中对BD 2有选择性的抑制剂，但对BD 1没有选择性，阻断了EndoMT。此外，显性负BRD 4特异性BD 2的表达完全消除了EndoMT。一致地，BRD 4敲低抑制TGF β 1刺激的ZEB 1蛋白-EndoMT中整合的转录因子-的增加。在体内，慢病毒基因转移的BRD 4 shRNA或显性负BRD 4特异性BD 2减轻新生内膜的发展，在大鼠颈静脉移植到carotid arteries.Conclusions：我们的数据揭示了BD 2结构域的BRD 4作为一个决定因素驱动EndoMT在体外和在体内的新生内膜形成。这些发现为BET生物学提供了新的见解，同时提供了特定BET结构域靶向作为限制新生内膜和延长静脉移植物通畅性的方法的前景。
Background: Vein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation.Methods and results: Repression of BRD4 expression abrogated TGF beta 1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4-specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGF beta 1-stimulated increase of ZEB1 protein - a transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugular veins grafted to carotid arteries.Conclusions: Our data reveal the BD2 domain of BRD4 as a determinant driving EndoMT in vitro and neointimal formation in vivo. These findings provide new insight into BET biology, while offering prospects of specific BET domain targeting as an approach to limiting neointima and extending vein graft patency.