CTRP1 Attenuates Cerebral Ischemia/Reperfusion Injury via the PERK Signaling Pathway.

Huizhi Fei,Wen Luo,Xiaodan Tan,Maozhu Liu,Pu Xiang,Qiong Wang,Junqing Yang,Chao Gu,Mengyuan Chen

doi:10.3389/fcell.2021.700854

Abstract

Cerebral ischemic stroke is one of the leading causes of death worldwide. Previous studies have shown that circulating levels of CTRP1 are upregulated in patients with acute ischemic stroke. However, the function of CTRP1 in neurons remains unclear. The purpose of this study was to explore the role of CTRP1 in cerebral ischemia reperfusion injury (CIRI) and to elucidate the underlying mechanism. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen–glucose deprivation/reoxygenation (OGD/R) models were used to simulate cerebral ischemic stroke in vivo and in vitro, respectively. CTRP1 overexpression lentivirus and CTRP1 siRNA were used to observe the effect of CTRP1 expression, and the PERK selective activator CCT020312 was used to activate the PERK signaling pathway. We found the decreased expression of CTRP1 in the cortex of MCAO/R-treated rats and OGD/R-treated primary cortical neurons. CTRP1 overexpression attenuated CIRI, accompanied by the reduction of apoptosis and suppression of the PERK signaling pathway. Interference with CTRP1 expression in vitro aggravated apoptotic activity and increased the expression of proteins involved in the PERK signaling pathway. Moreover, activating the PERK signaling pathway abolished the protective effects of CTRP1 on neuron injury induced by CIRI in vivo and in vitro. In conclusion, CTRP1 protects against CIRI by reducing apoptosis and endoplasmic reticulum stress (ERS) through inhibiting the PERK-dependent signaling pathway, suggesting that CTRP1 plays a crucial role in the pathogenesis of CIRI.

Highlights

Cerebral ischemic stroke is a serious cerebrovascular disease leading to serious neurological disability and death worldwide (Katan and Luft, 2018)
To the best of our knowledge, this is the first report describing the protective role of C1q/TNF-related protein1 (CTRP1) in neuron injury induced by cerebral ischemia and reperfusion
Our in vitro experiments indicated that CTRP1 overexpression attenuated neuron injury and apoptosis via the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway, while CTRP1 deficiency further aggravated neuron injury and apoptosis

Summary

Introduction

Cerebral ischemic stroke is a serious cerebrovascular disease leading to serious neurological disability and death worldwide (Katan and Luft, 2018). About 795,000 people experience a new or recurrent stroke, with ischemic stroke accounting for approximately 87% of the cases (Virani et al, 2021). It is urgent to find effective methods and drugs for the treatment of cerebral ischemic stroke. Ischemic stroke is caused by stenosis or occlusion of the cerebral supplying artery and transient or permanent local reduction of cerebral blood flow. It has been shown that millions of neurons and billions of synapses are destroyed during each minute of ischemia in patients (Saver, 2006; Desai et al, 2019). The critical treatment of ischemic stroke in the clinical setting

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