GanDouLing combined with Penicillamine improves cerebrovascular injury via PERK/eIF2α/CHOP endoplasmic reticulum stress pathway in the mouse model of Wilson's disease.

Yonghua Chen,Shijian Cao,Bo Zhang,Wenming Yang,Ni Liu,Wei Huang

doi:10.1042/bsr20180800

Abstract

We aim to investigate the function and mechanism of GanDouLing combinated with Penicillamine on cerebrovascular injury in Wilson’s disease (WD). ELISA was performed to analyze the expression of vascular injury factors. Pathological changes of cerebral vessels were observed by HE stain. Immunohistochemistry assays were performed to analyze the expression of ICAM-1, VCAM-1, and GRP78. Western blotting was measured to analyze the expression of caspase-3, caspase-12, PERK, eIF2α, and CHOP. Apoptosis was detected with TUNEL assay. The expression of vascular injury factors and ICAM-1, VCAM-1 was significantly increased by WD and markedly decreased in GanDouLing-Penicillamine group. The expression of caspase-3, caspase-12, PERK, eIF2α, and CHOP were obviously expressed in Wilson group, GanDouLing-Penicillamine suppressed apoptosis and endoplasmic reticulum (ER) stress. Our findings suggested that GanDouLing-Penicillamine improved cerebrovascular injury through PERK/eIF2α/CHOP ER stress pathway in the mouse model of WD.

Highlights

Wilson’s disease (WD) was first described by Kinnear Wilson in 1912 [1], which is an autosomal recessive metabolic disease caused by a mutation of ATP7B gene [2,3]
The results indicated that WD induced cerebrovascular injury in the mouse model
We identified cerebral vascular injury of mice caused by WD at the first attempt

Summary

Introduction

Wilson’s disease (WD) was first described by Kinnear Wilson in 1912 [1], which is an autosomal recessive metabolic disease caused by a mutation of ATP7B gene [2,3]. The ATP7B gene is a copper-transporting P-type ATPase (WD protein), mutation of this gene leads to the accumulation of copper in various tissues and organs, especially liver, brain, cornea, and kidneys [4]. Clinical manifestations vary from an asymptomatic state to acute hepatic failure, chronic liver disease, and neurological symptoms such as dystonia, tremor, dysarthria, and psychiatric disturbances [5,6]. WD has high lethality, but it is one of the few diseases that can be treated in congenital genetic diseases. It is meaningful and valuable to investigate the drug treatment of WD and the mechanism of related treatment in the clinic

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