Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts...

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Autores principales:	Changjun Yang, Bianca P. Lavayen, Lei Liu, Brian D. Sanz, Kelly M. DeMars, Jonathan Larochelle, Marjory Pompilus, Marcelo Febo, Yu-Yo Sun, Yi-Min Kuo, Mansour Mohamadzadeh, Susan A. Farr, Chia-Yi Kuan, Andrew A. Butler, Eduardo Candelario-Jalil
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Adropin Permanent middle cerebral artery occlusion Ischemic stroke Blood-brain barrier Neurovascular unit Neurobehavioral tests Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d7c0488233404b359c5b732943c3ea34
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spelling	oai:doaj.org-article:d7c0488233404b359c5b732943c3ea342021-11-26T04:28:59ZNeurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism2213-231710.1016/j.redox.2021.102197https://doaj.org/article/d7c0488233404b359c5b732943c3ea342021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003578https://doaj.org/toc/2213-2317Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.Changjun YangBianca P. LavayenLei LiuBrian D. SanzKelly M. DeMarsJonathan LarochelleMarjory PompilusMarcelo FeboYu-Yo SunYi-Min KuoMansour MohamadzadehSusan A. FarrChia-Yi KuanAndrew A. ButlerEduardo Candelario-JalilElsevierarticleAdropinPermanent middle cerebral artery occlusionIschemic strokeBlood-brain barrierNeurovascular unitNeurobehavioral testsMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102197- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Adropin Permanent middle cerebral artery occlusion Ischemic stroke Blood-brain barrier Neurovascular unit Neurobehavioral tests Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Adropin Permanent middle cerebral artery occlusion Ischemic stroke Blood-brain barrier Neurovascular unit Neurobehavioral tests Medicine (General) R5-920 Biology (General) QH301-705.5 Changjun Yang Bianca P. Lavayen Lei Liu Brian D. Sanz Kelly M. DeMars Jonathan Larochelle Marjory Pompilus Marcelo Febo Yu-Yo Sun Yi-Min Kuo Mansour Mohamadzadeh Susan A. Farr Chia-Yi Kuan Andrew A. Butler Eduardo Candelario-Jalil Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
description	Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.
format	article
author	Changjun Yang Bianca P. Lavayen Lei Liu Brian D. Sanz Kelly M. DeMars Jonathan Larochelle Marjory Pompilus Marcelo Febo Yu-Yo Sun Yi-Min Kuo Mansour Mohamadzadeh Susan A. Farr Chia-Yi Kuan Andrew A. Butler Eduardo Candelario-Jalil
author_facet	Changjun Yang Bianca P. Lavayen Lei Liu Brian D. Sanz Kelly M. DeMars Jonathan Larochelle Marjory Pompilus Marcelo Febo Yu-Yo Sun Yi-Min Kuo Mansour Mohamadzadeh Susan A. Farr Chia-Yi Kuan Andrew A. Butler Eduardo Candelario-Jalil
author_sort	Changjun Yang
title	Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
title_short	Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
title_full	Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
title_fullStr	Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
title_full_unstemmed	Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
title_sort	neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/d7c0488233404b359c5b732943c3ea34
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Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

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