Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium

Abstract The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subseque...

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Autores principales:	Luca Goitre, Peter V. DiStefano, Andrea Moglia, Nicholas Nobiletti, Eva Baldini, Lorenza Trabalzini, Julie Keubel, Eliana Trapani, Vladimir V. Shuvaev, Vladimir R. Muzykantov, Ingrid H. Sarelius, Saverio Francesco Retta, Angela J. Glading
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6fc3adc7ae70457492848b492ff196e1
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spelling	oai:doaj.org-article:6fc3adc7ae70457492848b492ff196e12021-12-02T12:32:38ZUp-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium10.1038/s41598-017-08373-42045-2322https://doaj.org/article/6fc3adc7ae70457492848b492ff196e12017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08373-4https://doaj.org/toc/2045-2322Abstract The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subsequent deficit in barrier function remains undefined. Previous studies have shown that loss of KRIT1 increases the production of reactive oxygen species (ROS) and exacerbates vascular permeability triggered by several inflammatory stimuli, but not TNF−α. We now show that endothelial ROS production directly contributes to the loss of barrier function in KRIT1 deficient animals and cells, as targeted antioxidant enzymes reversed the increase in permeability in KRIT1 heterozygous mice as shown by intravital microscopy. Rescue of the redox state restored responsiveness to TNF-α in KRIT1 deficient arterioles, but not venules. In vitro, KRIT1 depletion increased endothelial ROS production via NADPH oxidase signaling, up-regulated Nox4 expression, and promoted NF-κB dependent promoter activity. Recombinant yeast avenanthramide I, an antioxidant and inhibitor of NF-κB signaling, rescued barrier function in KRIT1 deficient cells. However, KRIT1 depletion blunted ROS production in response to TNF-α. Together, our data indicate that ROS signaling is critical for the loss of barrier function following genetic deletion of KRIT1.Luca GoitrePeter V. DiStefanoAndrea MogliaNicholas NobilettiEva BaldiniLorenza TrabalziniJulie KeubelEliana TrapaniVladimir V. ShuvaevVladimir R. MuzykantovIngrid H. SareliusSaverio Francesco RettaAngela J. GladingNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Luca Goitre Peter V. DiStefano Andrea Moglia Nicholas Nobiletti Eva Baldini Lorenza Trabalzini Julie Keubel Eliana Trapani Vladimir V. Shuvaev Vladimir R. Muzykantov Ingrid H. Sarelius Saverio Francesco Retta Angela J. Glading Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
description	Abstract The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subsequent deficit in barrier function remains undefined. Previous studies have shown that loss of KRIT1 increases the production of reactive oxygen species (ROS) and exacerbates vascular permeability triggered by several inflammatory stimuli, but not TNF−α. We now show that endothelial ROS production directly contributes to the loss of barrier function in KRIT1 deficient animals and cells, as targeted antioxidant enzymes reversed the increase in permeability in KRIT1 heterozygous mice as shown by intravital microscopy. Rescue of the redox state restored responsiveness to TNF-α in KRIT1 deficient arterioles, but not venules. In vitro, KRIT1 depletion increased endothelial ROS production via NADPH oxidase signaling, up-regulated Nox4 expression, and promoted NF-κB dependent promoter activity. Recombinant yeast avenanthramide I, an antioxidant and inhibitor of NF-κB signaling, rescued barrier function in KRIT1 deficient cells. However, KRIT1 depletion blunted ROS production in response to TNF-α. Together, our data indicate that ROS signaling is critical for the loss of barrier function following genetic deletion of KRIT1.
format	article
author	Luca Goitre Peter V. DiStefano Andrea Moglia Nicholas Nobiletti Eva Baldini Lorenza Trabalzini Julie Keubel Eliana Trapani Vladimir V. Shuvaev Vladimir R. Muzykantov Ingrid H. Sarelius Saverio Francesco Retta Angela J. Glading
author_facet	Luca Goitre Peter V. DiStefano Andrea Moglia Nicholas Nobiletti Eva Baldini Lorenza Trabalzini Julie Keubel Eliana Trapani Vladimir V. Shuvaev Vladimir R. Muzykantov Ingrid H. Sarelius Saverio Francesco Retta Angela J. Glading
author_sort	Luca Goitre
title	Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
title_short	Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
title_full	Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
title_fullStr	Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
title_full_unstemmed	Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
title_sort	up-regulation of nadph oxidase-mediated redox signaling contributes to the loss of barrier function in krit1 deficient endothelium
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6fc3adc7ae70457492848b492ff196e1
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Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium

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