NOX4

Official Full Name

NADPH oxidase 4

Organism

Homo sapiens

GeneID

50507

Background

This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

Synonyms

KOX; KOX-1; RENOX;

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Detailed Information

NOX4 was originally discovered as a kidney-specific NOX. NOX4 is expressed in different organelles, such as mitochondria, nuclei, and endoplasmic reticulum. Later, it was found that NOX4 is expressed in large amounts in the cardiovascular system, especially in endothelial cells and vascular smooth muscle cells. NOX4 is the most expressed NOX. In general, NOX4 activity is mainly regulated at the transcription level. In the cardiovascular system, stimulation of G protein-coupled receptor activators, growth factors, cytokines, oxidized low-density lipoprotein, and hypoxia-reoxygenation can activate NOX4.

Nox4 Figure 1. The role of NOX4 in angiogenesis. (Chen, C., et al. 2017)

The Role of NOX4

NOX4 plays an important role in a variety of cells. In cardiomyocytes and vascular smooth muscle cells, NOX4 activates the transcription factor NF-E2 related factor 2 (Nrf2) signaling pathway to regulate the antioxidant stress response. In endothelial cells, it activates endothelial nitric oxide synthase by activating the control gene transcriptional kinase/extracellular regulated protein kinase pathway, thereby promoting vascular cell survival. In endothelial cells under ischemic and inflammatory stress, NOX4 deficiency can attenuate the expression of the protein heme oxygenase-1 associated with inflammation and cell death. This dual effect of NOX4 is likely to depend on the level, duration, and subcellular localization of ROS under stress conditions. The activation of NOX4 is the main source of ROS in blood vessels, and the expression of NOX4 is mainly reflected in the level of ROS changes. Because ROS has the ability to target oxidative molecules, it can regulate molecular pathways, for example, to control protein activity through post-transcriptional translation modifications. Under cellular stress, oxidative stress regulates autophagy.

NOX4 and Atherosclerosis

NOX4 plays an important role in atherosclerosis as an endogenous anti-atherosclerotic enzyme that produces H₂O₂. Schürmann et al. hybridized NOX4-/-mice with ApoE-/-mice to construct a partial carotid artery ligation model and fed them on conventional foods and high-fat diets, respectively. The results showed that H₂O₂ production in the aortic ring of NOX4 and apolipoprotein E double knockout mice was lower than that of wild type mice. In addition, NOX4 deficiency can increase atherosclerosis, resulting in a significantly smaller carotid lumen than wild-type mice, and NOX4 deficiency in endothelial cells results in increased leukocyte adhesion. Therefore, NOX4 prevents vascular inflammation by limiting the angiogenesis of leukocytes, and ultimately weakens the development of atherosclerosis. Similar studies have demonstrated that NOX4 and apolipoprotein E double knockout animals appear to prevent the progression of atherosclerosis. Therefore, the current research proves that NOX4 has a beneficial effect on atherosclerosis.

NOX4 and Hypertension

The mechanism of essential hypertension is not fully understood, but many studies have shown the important role of NOX4 in the pathogenesis of hypertension. In the study of NOX4 and hypertension, to test whether the NOX4 enzyme affects angiotensin II-related hypertension, the researchers monitored systolic and diastolic arterial pressure in mice infused with angiotensin II wild-type and NOX4-inhibited. Angiotensin Ⅱ-induced pulse pressure was found to increase after blocking NOX4. In the angiotensin Ⅱ-induced mouse hypertension model, it was confirmed that down-regulation of NOX4 expression in the aorta can increase inflammation and endothelial dysfunction. Studies have also reported that NOX4 knockout mice develop pulmonary hypertension and endothelial dysfunction. Lu et al. exposed male SD rats to chronic intermittent hypoxia (CIH) for 21 days. It was found that compared to the blood pressure of the control group, the blood pressure of CIH rats began to increase 2 weeks after the start of the experiment, and then stabilized at a high level at the end of the 3rd week. Cysteine-treated rats attenuated this response, demonstrating that CIH-induced increase in blood pressure is mediated in part by NOX4-induced ROS production. By knocking out the NOX4 gene in salt-sensitive hypertension, the salt-sensitive rat model has a reduced blood pressure response to high salt. The above experiments have proved that in hypertension, NOX4 has a regulatory effect from different mechanisms and pathways.

References:

Schürmann, Christoph, Rezende, F. , Kruse, C. , Yasar, Y. , L?We, O. , & Fork, C. , et al. (2015). The nadph oxidase nox4 has anti-atherosclerotic functions. European Heart Journal, ehv460.
Chen, C. , Li, L. , Zhou, H. , & Min, W. . (2017). The role of nox4 and trx2 in angiogenesis and their potential cross-talk. Antioxidants, 6(2).
Lu, W. , Kang, J. , Hu, K. , Tang, S. , Zhou, X. , & Xu, L. , et al. (2017). The role of the nox4-derived ros-mediated rhoa/rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia. Sleep & Breathing, 149(4), A581-A581.

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