ROS generation by NOX4 is a key player in epithelial cell death leading to pulmonary fibrosis.

To understand the role of the superoxide-generating NADPH oxidase NOX1 in the vascular system, we have generated NOX1-deficient mice. NOX1-deficient mice had a moderately decreased basal blood pressure. In response to angiotensin II they showed an almost complete loss of the sustained blood pressure response, while the initial increase was conserved. NOX1-deficient mice showed a marked reduction in aortic media hypertrophy. Angiotensin II-induced smooth muscle cell proliferation was conserved, but there was a marked decrease in extracellular matrix accumulation. Our results establish a role for NOX1 in blood pressure regulation and vascular angiotensin II response.

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Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress-induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now. Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury. Methods: Wild-type and NOX1-and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O 2 for 72 hours. Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased. Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress-induced acute lung injury involving JNK and ERK pathways in mice.

Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.