Disease relevance of Nox1

• Finally, Nox1 partially restores superoxide production in neutrophils differentiating ex vivo from gp91(phox)-deficient CD34(+) peripheral blood-derived stem cells derived from patients with X-linked chronic granulomatous disease [1].
• Transduction with retrovirus encoding Nox1 restored activation and differentiation-dependent superoxide production in gp91(phox)-deficient PLB-985 cells, indicating close functional similarities to the phagocyte oxidase (phox) [1].
• Both inducible nitric oxide synthase and NADPH oxidase contribute to the control of virulent phase I Coxiella burnetii infections [2].
• Abrupt reoxygenation of microvascular endothelial cells after hypoxia activates ERK1/2 and JNK1, leading to NADPH oxidase-dependent oxidant production [3].
• NOXO1, which was upregulated in all three treatment groups, positively regulates the expression of a subunit of NADPH oxidase (NOX1), a major source of reactive oxygen species, and may play an important role in the pathogenesis of COPD [4].
• NADPH oxidase inhibitors blocked the production of lyso-PS in vitro, and accordingly, its generation in vivo by activated, murine neutrophils during zymosan-induced peritonitis was absent in mice lacking a functional NADPH oxidase (gp91phox-/-) [5].

Psychiatry related information on Nox1

• NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea [6].
• In mice lacking either NADPH oxidase or iNOS, however, B. abortus infected and persisted to the same extent as it did in congenic C57BL/6 mice up until 60 days postinfection, suggesting that these host defense mechanisms are not critical for limiting bacterial growth in the mouse [7].

High impact information on Nox1

• Therefore, NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens [8].
• The NADPH oxidase NOX2 is recruited to the DC's early phagosomes and mediates the sustained production of low levels of reactive oxygen species, causing active and maintained alkalinization of the phagosomal lumen [8].
• NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells [8].
• Here we show that COS-7 cells transfected with four NADPH oxidase components, but lacking H+ channels, produce O2- in the presence of Zn2+ concentrations that inhibit O2- production in neutrophils and eosinophils [9].
• The enzyme NADPH oxidase in phagocytes is important in the body's defence against microbes: it produces superoxide anions (O2-, precursors to bactericidal reactive oxygen species) [9].

Chemical compound and disease context of Nox1

• We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O2-sensor [10].
• NADPH oxidase may be involved in this process, because its expression and activity are upregulated by pressure overload and because myocardial hypertrophy caused by a subpressor infusion of angiotensin is attenuated in mice deficient in the gp91phox catalytic subunit of NADPH oxidase [11].
• Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes [12].
• Sleep and oxidative and proinflammatory responses were measured in adult mice either devoid of NADPH oxidase activity (gp91phox-null mice) or in which NADPH oxidase activity was systemically inhibited with apocynin osmotic pumps throughout hypoxia/reoxygenation [6].
• In the present study, we examined the significance of superoxide produced by macrophages by comparing the toxicity of acetaminophen in wild-type mice to mice deficient in gp91phox, a critical subunit of NADPH oxidase that is the primary source of phagocytic superoxide [13].

Biological context of Nox1

• A large number of genes, including many related to cell cycle, growth, and cancer (but unrelated to oxidative stress), were expressed in Nox1-expressing cells, and more than 60% of these returned to normal levels on coexpression of catalase [14].
• This study explores the role of reactive oxygen species (ROS) in regulating cell growth and transformation by Nox1 [14].
• Moreover, both RANKL-mediated ROS production and osteoclast differentiation were completely blocked in precursors depleted of Nox1 activity by RNA interference or by expressing a dominant-negative mutant of Rac1 [15].
• The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation [16].
• These studies demonstrate a significant functional homology (cofactor-dependent and activation-regulated superoxide production) between Nox1 and its closest homologue, gp91(phox), suggesting that targeted up-regulation of Nox1 expression in phagocytic cells could provide a novel approach in the molecular treatment of chronic granulomatous disease [1].

Anatomical context of Nox1

• In situ hybridization in mouse colon revealed high Nox1 expression within the lower two-thirds of colon crypts, where epithelial cells undergo proliferation and differentiation [1].
• Furthermore, coexpression of cytosolic components, p47(phox) and p67(phox), augments Nox1 activity in reconstituted K562 cells [1].
• We previously reported the cloning of Nox1 (NADPH oxidase1), a homolog of gp91phox, its expression in colon and vascular smooth muscle, and its oncogenic properties when overexpressed [Suh et al. (1999). Nature 401, 79-82] [17].
• Aortas of Tg(p22smc) mice had increased p22(phox) and Nox1 protein levels and produced more superoxide and H(2)O(2) [18].
• In neuroprogenitor, hypothalamic, and lymphoid cells, ERK1/2 activation is fully controlled by the NADPH oxidase-dependent ROS production [19].

Associations of Nox1 with chemical compounds

• H(2)O(2) concentration increased approximately 10-fold in Nox1-expressing cells, compared with <2-fold increase in O(2)(-) [14].
• We studied the expression and function of a recently described source of ROS, NAD(P)H oxidase 1 or Nox1, which has been associated with cell proliferation [1].
• In unstimulated VSMCs, phosphorothioate antisense oligonucleotides against Nox4 down-regulated mRNA expression of the subunit by 65% and attenuated superoxide production by 41% without affecting Nox1 expression [20].
• Vascular O2- and expression of the NADPH oxidase subunits p67phox and Nox1 were increased [21].
• Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice [22].

Physical interactions of Nox1

• First, we establish that 5-HT2B receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species (ROS) synthesis through NADPH oxidase activation in 1C115-HT and 1C11NE cells [23].
• Neuron-glia cultures from mice lacking a functional NADPH oxidase complex (PHOX-/-) were insensitive to substance P (10(-13)-10(-14) M) -induced loss of DA neuron function [24].

Enzymatic interactions of Nox1

• Rac1 and Rac2 are essential for the control of oxidative burst catalyzed by NADPH oxidase [25].
• However, p47-phox phosphorylated by calyculin A treatment lost its ability to activate NADPH oxidase [26].

Regulatory relationships of Nox1

• NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells [19].
• Consequently, inhibition of NADPH oxidase activity by diphenylen iodonium chloride (DPI) and apocynin abolished prooxidant- and chemical hypoxia-induced upregulation of CT-1 [27].
• These studies confirm that the four CGD-related phox mRNA components of NADPH oxidase are expressed early in embryonic development and the expression occurs in a consistent sequential fashion but only p22 phox protein appears in embryonic hemocytoblast [28].
• In the mesenteric arteries the expression of nox4 (4 weeks) and gp91phox (nox2) (8 weeks) subunits of NADPH oxidase from streptozotocin-apoE(-/-) were enhanced as were eNOS mRNA and protein (P<0.05) [29].
• NADPH-oxidase-driven oxygen radical production determines chondrocyte death and partly regulates metalloproteinase-mediated cartilage matrix degradation during interferon-gamma-stimulated immune complex arthritis [30].

Other interactions of Nox1

• The highest levels of p41 transcript are detected in the colon and in other gastrointestinal tissues that express Nox1, the predominant gp91phox homologue in these tissues [31].
• Furthermore, co-activation of JNK and Nox were sufficient to mimic the Rac mitogenic rescue [32].
• Nox is playing with a full deck in vascular smooth muscle, a commentary on "Noxa1 is a central component of the smooth muscle NADPH oxidase in mice" [33].
• Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47phox) [34].
• Proinflammatory mediators down-regulated Nox4 but did not affect Nox1 expression, so other factors must compensate to regulate superoxide production [20].

Analytical, diagnostic and therapeutic context of Nox1

• Human multitumor tissue array analysis confirmed colon-specific Nox1 expression, predominantly in differentiated epithelial tumors [1].
• Oxidative stress was assessed in aorta and mesenteric arteries by immunofluorescence labelling with dihydroethidium and levels of NADPH oxidase subunits and eNOS were determined by a real-time polymerase chain reaction protocol [29].
• Seeking evidence for the expression and function of the enzyme in primary hippocampal astrocytes, we confirmed the expression of the subunits of the phagocyte NADPH oxidase by Western blot analysis and by immunofluorescence and coexpression with the astrocyte-specific marker glial fibrillary acidic protein both in cultures and in vivo [35].
• METHODS AND RESULTS: To test the role of NADPH oxidase-dependent ROS in mediating pressure overload-induced myocardial hypertrophy, we subjected transgenic mice lacking gp91phox to chronic pressure overload caused by constriction of the ascending aorta [11].
• Western blotting of BPAECs and immunocytochemistry of BPAECs and rat and mouse lungs showed the presence of p47phox, a cytoplasmic component of NADPH oxidase and the putative target for PR-39 inhibition [36].

References