CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation.
CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation.
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CHIP 通过减轻坏死性凋亡和炎症来改善脑缺血再灌注损伤
DOI：
10.18632/aging.203774
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发表时间：
2021-12-14
期刊：
影响因子：
--
通讯作者：
Shi C
中科院分区：
文献类型：
--
作者：
Yao D;Zhang S;Hu Z;Luo H;Mao C;Fan Y;Tang M;Liu F;Shen S;Fan L;Li M;Shi J;Li J;Ma D;Xu Y;Shi C
缺血脑组织的血液再灌注可能导致脑缺血再灌注（CIR）损伤。坏死性凋亡和炎症已被证明参与CIR损伤的相关疾病过程。热休克蛋白70相互作用蛋白（CHIP）的E3泛素连接酶羧基末端能够调节多种细胞信号传导过程，包括坏死性凋亡和炎症。大量研究已证明CHIP对多种中枢神经系统（CNS）疾病具有神经保护作用。然而，CHIP对CIR损伤的影响尚未得到充分探究。我们假设CHIP可通过减轻CIR损伤过程中的坏死性凋亡和炎症发挥神经保护作用。在本研究中，具有C57BL/6背景的成年野生型（WT）C57BL/6小鼠和CHIP基因敲入（KI）小鼠以及神经组织中CHIP过表达的小鼠接受大脑中动脉闭塞（MCAO）手术以模拟CIR的发生。我们的数据表明，MCAO手术后梗死周围组织中的CHIP表达显著增加。与WT小鼠相比，CHIP KI小鼠显著改善了神经功能缺损评分，减少了脑梗死体积，并减轻了脑水肿和神经元损伤。同时，CHIP过表达减轻了MCAO手术诱导的坏死性凋亡和炎症。这些发现表明，CHIP的过表达可能通过减轻CIR损伤过程中的坏死性凋亡和炎症发挥神经保护作用，并且提高CHIP水平可能是脑血管疾病治疗的一种潜在策略。
Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.