Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury
Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury
复制标题
热休克蛋白 27 的内皮靶向过度表达可改善缺血性脑损伤后血脑屏障的破坏
DOI：
10.1073/pnas.1621174114
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发表时间：
2017-02-14
影响因子：
11.1
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Shi, Yejie;Jiang, Xiaoyan;Chen, Jun
缺血性中风和其他神经系统疾病期间形成血脑屏障（BBB）的内皮细胞（EC）所承受的损伤破坏了神经血管单元的结构和功能，并导致患者预后不良。我们最近报道脑微血管内皮细胞的结构畸变，即不受控制的肌动蛋白聚合和随后的连接蛋白的分解，是短暂局灶性缺血后再灌注30-60分钟内出现的早发性BBB破裂的可能原因。在这里，我们研究了热休克蛋白27（HSP 27）作为一个直接的肌动蛋白聚合的抑制剂和保护剂对缺血/再灌注（I/R）后血脑屏障破坏的作用。使用体内和体外模型，我们发现在内皮细胞内特异性过表达HSP 27-而不是在神经元内-改善I/R后1-24小时的BBB损伤。从机制上讲，热休克蛋白27抑制I/R诱导的异常肌动蛋白聚合，应力纤维的形成和连接蛋白易位在脑微血管内皮细胞，独立于其对细胞死亡的保护作用。通过在I/R后保持BBB的完整性，EC靶向的HSP 27过表达减弱了潜在破坏性中性粒细胞和巨噬细胞向脑实质的浸润，从而改善了长期卒中结局。值得注意的是，中风后早期给予连接到细胞穿透转导结构域（TAT-HSP 27）的HSP 27迅速升高脑微血管中的HSP 27水平，并改善I/R诱导的BBB破坏和随后的神经功能缺损。因此，本研究表明，HSP 27可以在EC水平发挥作用，以保持I/R脑损伤后BBB的完整性。HSP 27可能是缺血性中风和其他涉及BBB破坏的神经系统疾病的治疗剂。
The damage borne by the endothelial cells (ECs) forming the blood-brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs-namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30-60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs-but not within neurons-ameliorated BBB impairment 1-24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.