Chen Hao, Jing Yao, Xu Zhiming, Yang Dianxu, Ju Shiming, Guo Yan, Tian Hengli, Xue Lixia
Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Front Neurosci. 2020 Sep 8;14:925. doi: 10.3389/fnins.2020.00925. eCollection 2020.
Traumatic brain injury (TBI) could highly induce coagulopathy through breaking the dynamic balance between coagulation and fibrinolysis systems, which may be a major contributor to the progressive secondary injury cascade that occurs after TBI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition is reported to exert neuroprotection in TBI, making it a potential regulatory target involved in TBI-induced coagulation disorder. PTEN level is controlled in a major way by E3 ligase-mediated degradation through the ubiquitin-proteasome system. The C terminus of Hsc70-interacting protein (CHIP) has been shown to regulate proteasomal degradation and ubiquitination level of PTEN. In the present study, CHIP was overexpressed and knocked down in mouse brain microvascular endothelial cells (bEnd.3) and tissues during the early phase of TBI. cell proliferation, cell apoptosis, migration capacity, and invasion capacity were determined. The changes of procoagulant and apoptosis molecules after TBI were also detected as well as the micrangium density and blood-brain barrier permeability after TBI. results demonstrated that CHIP overexpression facilitated bEnd.3 cell proliferation, migration, and invasion and downregulated cell apoptosis and the expressions of procoagulant molecules through promoting PTEN ubiquitination in a simulated TBI model with stretch-induced injury treatment. experiments also demonstrated that CHIP overexpression suppressed post-TBI apoptosis and procoagulant protein expressions, as well as increased microvessel density, reduced hemorrhagic injury, and blood-brain barrier permeability. These findings suggested that the upregulation of CHIP may attenuate apoptosis and procoagulant activity, facilitate brain repair, and thus exerts neuroprotective effects in TBI.
创伤性脑损伤（TBI）可通过打破凝血和纤溶系统之间的动态平衡而高度诱导凝血病，这可能是TBI后发生的进行性继发性损伤级联反应的主要促成因素。据报道，10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）抑制在TBI中发挥神经保护作用，使其成为参与TBI诱导的凝血障碍的潜在调控靶点。PTEN水平主要通过泛素-蛋白酶体系统由E3连接酶介导的降解来控制。Hsc70相互作用蛋白（CHIP）的C末端已被证明可调节PTEN的蛋白酶体降解和泛素化水平。在本研究中，在TBI早期在小鼠脑微血管内皮细胞（bEnd.3）和组织中过表达和敲低CHIP。测定细胞增殖、细胞凋亡、迁移能力和侵袭能力。还检测了TBI后促凝和凋亡分子的变化以及TBI后微血管密度和血脑屏障通透性。结果表明，在拉伸诱导损伤处理的模拟TBI模型中，CHIP过表达通过促进PTEN泛素化促进bEnd.3细胞增殖、迁移和侵袭，并下调细胞凋亡和促凝分子的表达。实验还表明，CHIP过表达抑制TBI后的细胞凋亡和促凝蛋白表达，以及增加微血管密度、减少出血性损伤和血脑屏障通透性。这些发现表明，CHIP的上调可能减轻细胞凋亡和促凝活性，促进脑修复，从而在TBI中发挥神经保护作用。
