NOX1

Official Full Name

NADPH oxidase 1

Organism

Homo sapiens

GeneID

27035

Background

This gene encodes a member of the NADPH oxidase family of enzymes responsible for the catalytic one-electron transfer of oxygen to generate superoxide or hydrogen peroxide. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

Synonyms

MOX1; NOH1; NOH-1; GP91-2; NOH-1L;

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Detailed Information

The human NOX1 gene, also known as MOX1 (mitogenic oxidase 1) or NOH1 (NADPH oxidase homologue 1), is located in the X chromosome q22. The NOX1 protein contains 564 amino acids and is the first oxidase identified as a gp91phox homolog in mammals. It has 60% homology with NOX2. NOX1 is abundantly expressed in colonic epithelial cells, which not only regulates signal transduction related to tissue proliferation and cell differentiation, but also participates in host defense of the body.

Figure1. NADPH oxidase structure. (Filipciubotaru, F., et al. 2016)

Features of NOX1

NOX1 is found in almost all mammalian cells. Its function is to catalyze the reduction of oxygen molecules to form reactive oxygen species such as superoxide or peroxide. NOX1 catalyzed ROS plays an important role in many physiological processes. ROS plays a key role in respiratory outbreaks mediated by pathogenic microorganisms. In addition to immune effects, ROS catalyzed by NOX1 is also involved in physiological processes such as cell proliferation, apoptosis, angiogenesis, oxidative modification of endocrine and extracellular matrix, and regulation of signaling pathways. NOX1 catalyzes the production of ROS and plays an important role in the inflammatory process. At the site of inflammation, ROS production in neutrophils increases, causing vascular endothelial dysfunction and tissue damage.

Nox1 and Disease

Inhibiting the renin-angiotensin-aldosterone system (renin-angiotenin-aldostrome, RAAS) can benefit patients with hypertension, possibly by reducing the oxidative stress triggered by long-term harmful stimuli. For example, activating RAAS can increase the expression of NOX1, NOX2 and other subunits. In transgenic mice with overexpression of vascular smooth muscle NOX1, it was found that angiotensin II has a significantly enhanced role in regulating vascular hypertrophy and increased blood pressure. When the NOX1 gene is defective, blood vessel O2-production is reduced and the aforementioned regulatory effects are weakened. Animal experiments suggest that migration and proliferation of vascular smooth muscle cells are reduced in the NOX1 knockout rat model. In addition, knockdown of NOX1 in the arteriosclerotic rat model can reduce the expression of ROS and reduce the area of aortic plaque.

The expression of NOX2 and NOX1 in fibrotic liver was significantly increased, but NOX2 could play a role in promoting fibrosis in both endogenous liver cells and bone marrow-transformed liver cells. NOX1 mainly mediates fibrosis in endogenous liver cells, such as HSC and hepatocytes. NOX1 knockout (NOX1KO) mice were used to study the role of NOX1 in the development of liver fibrosis. It was found that after bile duct ligation (BDL), the expression level of type I collagen mRNA, the content of hydroxyproline, the number of activated HSCs, and the degree of liver fibrosis in the liver of NOX1KO mice were significantly reduced. In addition, research also found that NOX1-derived ROS can oxidize phosphatidylinositol-3 kinase/Akt (PI3K/Akt) signaling pathways to negatively regulate factor-phosphatase and tonin phosphatase and tension homologue (PTEN) and inactivate it, and then increase the expression of Akt/FOXO4/p27kip1 signaling pathway to promote the proliferation of HSCs and accelerate the development of liver fibrosis.

Nox1 Inhibitor

It was found that GKT137831 is a highly specific inhibitor of NOX1/NOX4, and its inhibitory effect on NOX4 and NOX1 is better than DPI (a wide range of flavin protein inhibitors). Regardless of the prophylactic or therapeutic use of GKT137831, the generation of ROS in the liver, the levels of NOX1 and NOX4 genes, the expression of fibrosis markers, and the apoptosis of liver cells were significantly reduced. As a class of selective NOX1 and NOX4 inhibitors, pyrazolopyridine dione compounds are expected to develop into a new class of therapeutic drugs for diabetic nephropathy and idiopathic fibrosis. NOXA1ds is a NOX1 inhibitor. Its 11 amino acid sequence is the same as the amino acid sequence of NOXA1 and NOX1 binding region. It can specifically bind to NOX1 and inhibit NOX1 activation. Biological studies have found that NOXA1ds can selectively inhibit NOX1, but has no effect on NOX2, NOX4 and NOX5.

References:

Filipciubotaru, F. , Manciuc, C. , Stoleru, G. , & Foia, L. . (2016). Nadph oxidase: structure and activation mechanisms (review). Note I.
Matsumoto, M. , Katsuyama, M. , Iwata, K. , Ibi, M. , Zhang, J. , & Zhu, K. , et al. (2014). Characterization of n-glycosylation sites on the extracellular domain of nox1/nadph oxidase. Free Radical Biology and Medicine, 68, 196-204.
Benjamin J. Dickson, Mohamed I. Gatie, Danielle M. Spice, & Gregory M. Kelly. (2017). Nox1 and nox4 are required for the differentiation of mouse f9 cells into extraembryonic endoderm. Plos One, 12(2), e0170812.

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