Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke
Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke作者机构：Department of Neurology&PsychologyShenzhen Traditional Chinese Medicine HospitalThe Fourth Clinical Medical College of Guangzhou University of Chinese MedicineShenzhenGuangdong ProvinceChina Department of Cardiothoracic SurgeryShenzhen Traditional Chinese Medicine HospitalThe Fourth Clinical Medical College of Guangzhou University of Chinese MedicineShenzhenGuangdong ProvinceChina Department of NeurologyThe University of Texas Health Science Center at HoustonHoustonTXUSA Department of NephrologyShenzhen Traditional Chinese Medicine HospitalThe Fourth Clinical Medical College of Guangzhou University of Chinese MedicineShenzhenGuangdong ProvinceChina Department of Anesthesiology and Pain MedicineThe Affiliated Hospital of Jiaxing UniversityJiaxingZhejiang ProvinceChina
出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)
年 卷 期：2023年第18卷第8期
页 面：1743-1749页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学]
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.81(to LSX)。
主 题：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
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 BBB,alleviating brain injury,and improving post-stroke prognosis.
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