Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke  

作　　者：Xiu-De Qin Tai-Qin Yang Jing-Hui Zeng Hao-Bin Cai Shao-Hua Qi Jian-Jun Jiang Ying Cheng Long-Sheng Xu Fan Bu 

机构地区：[1]Department of Neurology&Psychology,Shenzhen Traditional Chinese Medicine Hospital,The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong Province,China [2]Department of Cardiothoracic Surgery,Shenzhen Traditional Chinese Medicine Hospital,The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong Province,China [3]Department of Neurology,The University of Texas Health Science Center at Houston,Houston,TX,USA [4]Department of Nephrology,Shenzhen Traditional Chinese Medicine Hospital,The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong Province,China [5]Department of Anesthesiology and Pain Medicine,The Affiliated Hospital of Jiaxing University,Jiaxing,Zhejiang Province,China

出　　处：《Neural Regeneration Research》2023年第8期1743-1749,共7页中国神经再生研究（英文版）

基　　金：supported by Research Start-up Funding of Shenzhen Traditional Chinese Medicine Hospital,No.2021-07(to FB);Sanming Project of Medicine in Shenzhen,No.SZZYSM 202111011(to XDQ and FB);Key Discipline Established by Zhejiang Province,Jiaxing City Jointly-Pain Medicine,No.2019-ss-ttyx(to LSX);Jiaxing Key Laboratory of Neurology and Pain Medicine,No.[2014]81(to LSX)。

摘　　要：Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BB

关 键 词：blood-brain barrier brain injury cerebral ischemia endothelial cells extracellular signal-regulated kinase 1/2 functional recovery mitogenactivated protein kinase phosphatase 1 OCCLUDIN oxygen and glucose deprivation transient middle cerebral artery occlusion 

分 类 号：R741[医药卫生—神经病学与精神病学]