CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation.

Dabao Yao,Mengjie Li,Yuming Xu,Dongrui Ma,Chengyuan Mao,Jiadi Li,Si Shen,Mibo Tang,Haiyang Luo,Changhe Shi,Fen Liu,Jingjing Shi,Zhengwei Hu,Yu Fan,Shuo Zhang,Liyuan Fan

doi:10.18632/aging.203774

Abstract

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.

Highlights

Stroke is a serious cerebrovascular disease associated with aging, and approximately 80% of stroke events are classified as ischemic strokes [1]
These results indicated that carboxyl terminus of Hsp70-interacting protein (CHIP) expression was upregulated after middle cerebral artery occlusion (MCAO), and neurons might be the primary cellular sources for CHIP induction
MCAO surgery and sham surgery groups (Figure 3E). These results indicated that CHIP overexpression alleviates brain injury after MCAO surgery

Summary

Introduction

Stroke is a serious cerebrovascular disease associated with aging, and approximately 80% of stroke events are classified as ischemic strokes [1]. Mechanical thrombectomy and thrombolytic therapy using tissue plasminogen activator are two common methods to restore blood supply of ischemic brain tissue in ischemic stroke treatments [2]. Achieving blood reperfusion of the ischemic brain tissue by mechanical thrombectomy or thrombolytic therapy may cause secondary brain injury, known as cerebral ischemia-reperfusion (CIR) injury [3]. Studies have shown that CIR injury involves multiple mechanisms, such as mitochondrial damage, energy failure, calcium overload, and www.aging-us.com inflammation [4,5,6]. These mechanisms can induce neuronal cell death, which causes neurological deficits. Strategies to reduce neuronal cell death may be conducive to treating brain injury after CIR

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