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NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow

First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TN...

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Autores principales: Li, Y., Cifuentes-Pagano, E., DeVallance, E.R., de Jesus, D.S., Sahoo, S., Meijles, D.N., Koes, D., Camacho, C.J., Ross, M., St Croix, C., Pagano, P.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435978/
https://www.ncbi.nlm.nih.gov/pubmed/30897521
http://dx.doi.org/10.1016/j.redox.2019.101143
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author Li, Y.
Cifuentes-Pagano, E.
DeVallance, E.R.
de Jesus, D.S.
Sahoo, S.
Meijles, D.N.
Koes, D.
Camacho, C.J.
Ross, M.
St Croix, C.
Pagano, P.J.
author_facet Li, Y.
Cifuentes-Pagano, E.
DeVallance, E.R.
de Jesus, D.S.
Sahoo, S.
Meijles, D.N.
Koes, D.
Camacho, C.J.
Ross, M.
St Croix, C.
Pagano, P.J.
author_sort Li, Y.
collection PubMed
description First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TNFα-induced endothelial reactive oxygen species (ROS) generation and pro-inflammatory signaling would be ameliorated by targeting Nox2. Herein, we in silico-modelled two first-in-class Nox2 inhibitors developed in our laboratory, explored their cellular mechanism of action and tested their efficacy in in vitro and mouse in vivo models of inflammation. Our data show that these inhibitors (CPP11G and CPP11H) disrupted canonical Nox2 organizing factor, p47(phox), translocation to Nox2 in the plasma membrane; and abolished ROS production, markedly attenuated stress-responsive MAPK signaling and downstream AP-1 and NFκB nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNFα-induced ROS and inflammation were ameliorated by targeted Nox2 inhibition, which, in turn, improved hind-limb blood flow. These studies identify a proximal role for Nox2 in propagated inflammatory signaling and support therapeutic value of Nox2 inhibitors in inflammatory disease.
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spelling pubmed-64359782019-04-08 NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow Li, Y. Cifuentes-Pagano, E. DeVallance, E.R. de Jesus, D.S. Sahoo, S. Meijles, D.N. Koes, D. Camacho, C.J. Ross, M. St Croix, C. Pagano, P.J. Redox Biol Research Paper First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TNFα-induced endothelial reactive oxygen species (ROS) generation and pro-inflammatory signaling would be ameliorated by targeting Nox2. Herein, we in silico-modelled two first-in-class Nox2 inhibitors developed in our laboratory, explored their cellular mechanism of action and tested their efficacy in in vitro and mouse in vivo models of inflammation. Our data show that these inhibitors (CPP11G and CPP11H) disrupted canonical Nox2 organizing factor, p47(phox), translocation to Nox2 in the plasma membrane; and abolished ROS production, markedly attenuated stress-responsive MAPK signaling and downstream AP-1 and NFκB nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNFα-induced ROS and inflammation were ameliorated by targeted Nox2 inhibition, which, in turn, improved hind-limb blood flow. These studies identify a proximal role for Nox2 in propagated inflammatory signaling and support therapeutic value of Nox2 inhibitors in inflammatory disease. Elsevier 2019-02-15 /pmc/articles/PMC6435978/ /pubmed/30897521 http://dx.doi.org/10.1016/j.redox.2019.101143 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Li, Y.
Cifuentes-Pagano, E.
DeVallance, E.R.
de Jesus, D.S.
Sahoo, S.
Meijles, D.N.
Koes, D.
Camacho, C.J.
Ross, M.
St Croix, C.
Pagano, P.J.
NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title_full NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title_fullStr NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title_full_unstemmed NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title_short NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
title_sort nadph oxidase 2 inhibitors cpp11g and cpp11h attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435978/
https://www.ncbi.nlm.nih.gov/pubmed/30897521
http://dx.doi.org/10.1016/j.redox.2019.101143
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