期刊
REDOX BIOLOGY
卷 22, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2019.101143
关键词
NADPH oxidase; Reactive oxygen species; Small-molecule inhibitor; Vascular inflammation; Endothelial dysfunction
资金
- National Institutes of Health (NIH) [R01HL079207, P01HL103455-01]
- AHA [18TPA34170069]
- NIH [2R01GM097082]
- AHA fellowship [17POST33660330]
- Institute for Transfusion Medicine
- Hemophilia Center of Western Pennsylvania
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 TNF alpha-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 NF kappa B nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNF alpha-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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