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1.
Redox Biol ; 22: 101143, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30897521

RESUMO

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, p47phox, 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.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasculite/metabolismo , Animais , Biomarcadores , Adesão Celular , Linhagem Celular , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NADPH Oxidase 2/química , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Fator de Transcrição AP-1/metabolismo , Vasculite/tratamento farmacológico , Vasculite/etiologia , Vasculite/patologia
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