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Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure

Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxid...

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Autores principales: Chignalia, Andreia Z., Isbatan, Ayman, Patel, Milan, Ripper, Richard, Sharlin, Jordan, Shosfy, Joelle, Borlaug, Barry A., Dull, Randal O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250809/
https://www.ncbi.nlm.nih.gov/pubmed/30355657
http://dx.doi.org/10.1042/BSR20181239
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author Chignalia, Andreia Z.
Isbatan, Ayman
Patel, Milan
Ripper, Richard
Sharlin, Jordan
Shosfy, Joelle
Borlaug, Barry A.
Dull, Randal O.
author_facet Chignalia, Andreia Z.
Isbatan, Ayman
Patel, Milan
Ripper, Richard
Sharlin, Jordan
Shosfy, Joelle
Borlaug, Barry A.
Dull, Randal O.
author_sort Chignalia, Andreia Z.
collection PubMed
description Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension. Methods and results: Male Sprague–Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (P(pa)) that were associated with a rapid fall in P(a)O(2), and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling. Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.
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spelling pubmed-62508092018-12-04 Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure Chignalia, Andreia Z. Isbatan, Ayman Patel, Milan Ripper, Richard Sharlin, Jordan Shosfy, Joelle Borlaug, Barry A. Dull, Randal O. Biosci Rep Research Articles Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension. Methods and results: Male Sprague–Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (P(pa)) that were associated with a rapid fall in P(a)O(2), and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling. Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF. Portland Press Ltd. 2018-11-23 /pmc/articles/PMC6250809/ /pubmed/30355657 http://dx.doi.org/10.1042/BSR20181239 Text en © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Chignalia, Andreia Z.
Isbatan, Ayman
Patel, Milan
Ripper, Richard
Sharlin, Jordan
Shosfy, Joelle
Borlaug, Barry A.
Dull, Randal O.
Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title_full Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title_fullStr Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title_full_unstemmed Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title_short Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure
title_sort pressure-dependent nos activation contributes to endothelial hyperpermeability in a model of acute heart failure
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250809/
https://www.ncbi.nlm.nih.gov/pubmed/30355657
http://dx.doi.org/10.1042/BSR20181239
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