Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke

Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood‐brain barrier disruption. Recently, we have shown that endothelial permeability is mediated...

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Autores principales:	Susmita Bhattarai, Sudha Sharma, Hosne Ara, Utsab Subedi, Grace Sun, Chun Li, Md. Shenuarin Bhuiyan, Christopher Kevil, William P. Armstrong, Miles T. Minvielle, Sumitra Miriyala, Manikandan Panchatcharam
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	autotaxin blood‐brain barrier ischemic stroke lysophosphatidic acid permeability superoxide radicals Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/9ed857d98fda4039b004bbe060d052e1
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spelling	oai:doaj.org-article:9ed857d98fda4039b004bbe060d052e12021-11-23T11:36:34ZDisrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke10.1161/JAHA.121.0215112047-9980https://doaj.org/article/9ed857d98fda4039b004bbe060d052e12021-09-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.121.021511https://doaj.org/toc/2047-9980Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood‐brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood‐brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24‐hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood‐brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7‐fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4‐fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P<0.01) basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity. Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP‐LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin‐LPA signaling blockade attenuates blood‐brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke.Susmita BhattaraiSudha SharmaHosne AraUtsab SubediGrace SunChun LiMd. Shenuarin BhuiyanChristopher KevilWilliam P. ArmstrongMiles T. MinvielleSumitra MiriyalaManikandan PanchatcharamWileyarticleautotaxinblood‐brain barrierischemic strokelysophosphatidic acidpermeabilitysuperoxide radicalsDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autotaxin blood‐brain barrier ischemic stroke lysophosphatidic acid permeability superoxide radicals Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	autotaxin blood‐brain barrier ischemic stroke lysophosphatidic acid permeability superoxide radicals Diseases of the circulatory (Cardiovascular) system RC666-701 Susmita Bhattarai Sudha Sharma Hosne Ara Utsab Subedi Grace Sun Chun Li Md. Shenuarin Bhuiyan Christopher Kevil William P. Armstrong Miles T. Minvielle Sumitra Miriyala Manikandan Panchatcharam Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
description	Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood‐brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood‐brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24‐hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood‐brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7‐fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4‐fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P<0.01) basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity. Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP‐LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin‐LPA signaling blockade attenuates blood‐brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke.
format	article
author	Susmita Bhattarai Sudha Sharma Hosne Ara Utsab Subedi Grace Sun Chun Li Md. Shenuarin Bhuiyan Christopher Kevil William P. Armstrong Miles T. Minvielle Sumitra Miriyala Manikandan Panchatcharam
author_facet	Susmita Bhattarai Sudha Sharma Hosne Ara Utsab Subedi Grace Sun Chun Li Md. Shenuarin Bhuiyan Christopher Kevil William P. Armstrong Miles T. Minvielle Sumitra Miriyala Manikandan Panchatcharam
author_sort	Susmita Bhattarai
title	Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
title_short	Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
title_full	Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
title_fullStr	Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
title_full_unstemmed	Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke
title_sort	disrupted blood‐brain barrier and mitochondrial impairment by autotaxin–lysophosphatidic acid axis in postischemic stroke
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/9ed857d98fda4039b004bbe060d052e1
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Disrupted Blood‐Brain Barrier and Mitochondrial Impairment by Autotaxin–Lysophosphatidic Acid Axis in Postischemic Stroke

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