Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood-brain barrier integrity.
Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood-brain barrier integrity.
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DOI：
10.1186/s12974-022-02533-8
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发表时间：
2022-06-27
影响因子：
9.3
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中科院分区：
文献类型：
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含溴结构域蛋白4(BRD4)是溴结构域和末端外结构域(BET)蛋白家族的一员，在调节与卒中发生发展密切相关的炎症和氧化应激中起着至关重要的作用。因此，BRD4的阻断吸引了越来越多的人对包括中风在内的相关神经疾病的兴趣。DBET1是一种新型高效的蛋白水解靶向嵌合体(PROTAC)BRD4降解剂。我们假设dBET1通过减少炎症和氧化应激并保护血脑屏障(BBB)的完整性来保护短暂性局灶性脑中风小鼠模型的脑损伤和神经功能障碍。卒中后4小时开始的缺血后dBET1治疗显著改善了严重的神经功能缺失，并在卒中后48小时缩小了脑梗塞体积。DBET1可显著减轻中风后的炎症和氧化应激，表现为多种促炎细胞因子和趋化因子，包括IL-1β、IL-6、肿瘤坏死因子-α、CCL2、CXCL1和CXCL10，以及氧化损伤标记物4-羟基壬烯醛(4-HNE)和gp91Phox以及抗氧化蛋白SOD2和GPX1。同时，dBET1治疗可显著减轻卒中所致的血脑屏障破坏、基质金属蛋白酶-9水平升高、中性粒细胞浸润和ICAM-1的升高。缺血后给予dBET1也减轻了缺血诱导的小胶质细胞和星形胶质细胞的反应性胶质增生。总体而言，这些发现表明，dBET1对BRD4的降解改善了急性中风的预后，这与减少神经炎症和氧化应激以及保持血脑屏障的完整性有关。这项研究确定了BET蛋白在导致缺血性脑损伤的机制中的一个新的作用，这可以被用来开发新的治疗方法。网上版载有补充材料，可在10.1186/s12974-022-02533-8查阅。
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, plays a crucial role in regulating inflammation and oxidative stress that are tightly related to stroke development and progression. Consequently, BRD4 blockade has attracted increasing interest for associated neurological diseases, including stroke. dBET1 is a novel and effective BRD4 degrader through the proteolysis-targeting chimera (PROTAC) strategy. We hypothesized that dBET1 protects against brain damage and neurological deficits in a transient focal ischemic stroke mouse model by reducing inflammation and oxidative stress and preserving the blood–brain barrier (BBB) integrity. Post-ischemic dBET1 treatment starting 4 h after stroke onset significantly ameliorated severe neurological deficits and reduced infarct volume 48 h after stroke. dBET1 markedly reduced inflammation and oxidative stress after stroke, indicated by multiple pro-inflammatory cytokines and chemokines including IL-1β, IL-6, TNF-α, CCL2, CXCL1 and CXCL10, and oxidative damage markers 4-hydroxynonenal (4-HNE) and gp91phox and antioxidative proteins SOD2 and GPx1. Meanwhile, stroke-induced BBB disruption, increased MMP-9 levels, neutrophil infiltration, and increased ICAM-1 were significantly attenuated by dBET1 treatment. Post-ischemic dBET1 administration also attenuated ischemia-induced reactive gliosis in microglia and astrocytes. Overall, these findings demonstrate that BRD4 degradation by dBET1 improves acute stroke outcomes, which is associated with reduced neuroinflammation and oxidative stress and preservation of BBB integrity. This study identifies a novel role of BET proteins in the mechanisms resulting in ischemic brain damage, which can be leveraged to develop novel therapies. The online version contains supplementary material available at 10.1186/s12974-022-02533-8.
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