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MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guan...

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Autores principales: Ghimire, Kedar, Zaric, Jelena, Alday-Parejo, Begoña, Seebach, Jochen, Bousquenaud, Mélanie, Stalin, Jimmy, Bieler, Grégory, Schnittler, Hans-Joachim, Rüegg, Curzio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562810/
https://www.ncbi.nlm.nih.gov/pubmed/31035633
http://dx.doi.org/10.3390/cells8050388
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author Ghimire, Kedar
Zaric, Jelena
Alday-Parejo, Begoña
Seebach, Jochen
Bousquenaud, Mélanie
Stalin, Jimmy
Bieler, Grégory
Schnittler, Hans-Joachim
Rüegg, Curzio
author_facet Ghimire, Kedar
Zaric, Jelena
Alday-Parejo, Begoña
Seebach, Jochen
Bousquenaud, Mélanie
Stalin, Jimmy
Bieler, Grégory
Schnittler, Hans-Joachim
Rüegg, Curzio
author_sort Ghimire, Kedar
collection PubMed
description Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production.
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spelling pubmed-65628102019-06-17 MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress Ghimire, Kedar Zaric, Jelena Alday-Parejo, Begoña Seebach, Jochen Bousquenaud, Mélanie Stalin, Jimmy Bieler, Grégory Schnittler, Hans-Joachim Rüegg, Curzio Cells Article Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production. MDPI 2019-04-27 /pmc/articles/PMC6562810/ /pubmed/31035633 http://dx.doi.org/10.3390/cells8050388 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ghimire, Kedar
Zaric, Jelena
Alday-Parejo, Begoña
Seebach, Jochen
Bousquenaud, Mélanie
Stalin, Jimmy
Bieler, Grégory
Schnittler, Hans-Joachim
Rüegg, Curzio
MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title_full MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title_fullStr MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title_full_unstemmed MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title_short MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
title_sort magi1 mediates enos activation and no production in endothelial cells in response to fluid shear stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562810/
https://www.ncbi.nlm.nih.gov/pubmed/31035633
http://dx.doi.org/10.3390/cells8050388
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