Design and evaluation of EphrinA1 mutants with cerebral protective effect

Abstract The activation of EphA2 receptor by its natural ligand EphrinA1 causes blood brain barrier dysfunction, and inactivation of EphA2 reduces BBB damage in ischemic stroke. Thus, EphA2 targeted antagonists may serve as neuroprotective agents. We engineered four mutants of EphrinA1, EM1, EM2, EM...

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Autores principales:	Yuanjun Zhu, Yuanqing Gao, Danping Zheng, Mengyang Shui, Kuai Yu, Xiaoyan liu, Yuan Lin, Li Su, Wenxing Yang, Yinye Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8334f8cc4c504f67a9c7b3affe658951
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spelling	oai:doaj.org-article:8334f8cc4c504f67a9c7b3affe6589512021-12-02T16:06:32ZDesign and evaluation of EphrinA1 mutants with cerebral protective effect10.1038/s41598-017-02091-72045-2322https://doaj.org/article/8334f8cc4c504f67a9c7b3affe6589512017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02091-7https://doaj.org/toc/2045-2322Abstract The activation of EphA2 receptor by its natural ligand EphrinA1 causes blood brain barrier dysfunction, and inactivation of EphA2 reduces BBB damage in ischemic stroke. Thus, EphA2 targeted antagonists may serve as neuroprotective agents. We engineered four mutants of EphrinA1, EM1, EM2, EM3 and EM4, respectively. The computational analysis showed that these four mutants were capable of interacting with EphA2. Their potential neuroprotective effects were examined in mouse focal ischemia/reperfusion (I/R) model. EM2 exhibited strong neuroprotective effects, including reduced brain infarct volume, neuronal apoptosis, cerebral edema, and improved neurological scores. The EM2-mediated protection was associated with a comparative decrease in BBB leakage, inflammatory infiltration, and higher expression levels of tight junction proteins, such as zonula occludens-1 and Occludin. I/R-induced high expression of Rho-associated protein kinase 2 (ROCK2) was down-regulated after EM2 treatment. Moreover, EM2 reduced agonist doxazosin-induced EphA2 phosphorylation and cells rounding in PC3 cells, indicating EphA2-antagonizing activity of EM2. These finding provided evidences of the neuroprotection of EphA2 antagonist and a novel approach for ischemic stroke treatment. These results also suggested that a receptor agonist can be switched to an antagonist by substituting one or more relevant residues.Yuanjun ZhuYuanqing GaoDanping ZhengMengyang ShuiKuai YuXiaoyan liuYuan LinLi SuWenxing YangYinye WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuanjun Zhu Yuanqing Gao Danping Zheng Mengyang Shui Kuai Yu Xiaoyan liu Yuan Lin Li Su Wenxing Yang Yinye Wang Design and evaluation of EphrinA1 mutants with cerebral protective effect
description	Abstract The activation of EphA2 receptor by its natural ligand EphrinA1 causes blood brain barrier dysfunction, and inactivation of EphA2 reduces BBB damage in ischemic stroke. Thus, EphA2 targeted antagonists may serve as neuroprotective agents. We engineered four mutants of EphrinA1, EM1, EM2, EM3 and EM4, respectively. The computational analysis showed that these four mutants were capable of interacting with EphA2. Their potential neuroprotective effects were examined in mouse focal ischemia/reperfusion (I/R) model. EM2 exhibited strong neuroprotective effects, including reduced brain infarct volume, neuronal apoptosis, cerebral edema, and improved neurological scores. The EM2-mediated protection was associated with a comparative decrease in BBB leakage, inflammatory infiltration, and higher expression levels of tight junction proteins, such as zonula occludens-1 and Occludin. I/R-induced high expression of Rho-associated protein kinase 2 (ROCK2) was down-regulated after EM2 treatment. Moreover, EM2 reduced agonist doxazosin-induced EphA2 phosphorylation and cells rounding in PC3 cells, indicating EphA2-antagonizing activity of EM2. These finding provided evidences of the neuroprotection of EphA2 antagonist and a novel approach for ischemic stroke treatment. These results also suggested that a receptor agonist can be switched to an antagonist by substituting one or more relevant residues.
format	article
author	Yuanjun Zhu Yuanqing Gao Danping Zheng Mengyang Shui Kuai Yu Xiaoyan liu Yuan Lin Li Su Wenxing Yang Yinye Wang
author_facet	Yuanjun Zhu Yuanqing Gao Danping Zheng Mengyang Shui Kuai Yu Xiaoyan liu Yuan Lin Li Su Wenxing Yang Yinye Wang
author_sort	Yuanjun Zhu
title	Design and evaluation of EphrinA1 mutants with cerebral protective effect
title_short	Design and evaluation of EphrinA1 mutants with cerebral protective effect
title_full	Design and evaluation of EphrinA1 mutants with cerebral protective effect
title_fullStr	Design and evaluation of EphrinA1 mutants with cerebral protective effect
title_full_unstemmed	Design and evaluation of EphrinA1 mutants with cerebral protective effect
title_sort	design and evaluation of ephrina1 mutants with cerebral protective effect
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8334f8cc4c504f67a9c7b3affe658951
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Design and evaluation of EphrinA1 mutants with cerebral protective effect

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