NOX5: Molecular biology and pathophysiology

Abstract

New Findings What is the topic of this review? This review provides a comprehensive overview of Nox5 from basic biology to human disease and highlights unique features of this Nox isoform What advances does it highlight? Major advances in Nox5 biology relate to crystallization of the molecule and new insights into the pathophysiological role of Nox5. Recent discoveries have unravelled the crystal structure of Nox5, the first Nox isoform to be crystalized. This provides new opportunities to develop drugs or small molecules targeted to Nox5 in an isoform‐specific manner, possibly for therapeutic use. Moreover genome wide association studies (GWAS) identified Nox5 as a new blood pressure‐associated gene and studies in mice expressing human Nox5 in a cell‐specific manner have provided new information about the (patho) physiological role of Nox5 in the cardiovascular system and kidneys. Nox5 seems to be important in the regulation of vascular contraction and kidney function. In cardiovascular disease and diabetic nephropathy, Nox5 activity is increased and this is associated with increased production of reactive oxygen species and oxidative stress implicated in tissue damage. Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca 2+ , it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic ...

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

“…Evidence that Nox1, Nox2 and Nox4 isoforms have a causal role in various disorders has continued to expand, but far less understood is the role of Nox5 in disease including retinopathy. 18 Since Nox5 is absent from the rodent genome, mouse models expressing the human Nox5 gene have been developed. [40][41][42] In transgenic mice expressing Nox5 under the control of the Tie2 promoter, disruption of the blood-brain barrier due to stroke was increased in transgenic Nox5 mice, indicating a critical role for Nox5 in vascular integrity in the central nervous system.…”

“…17 Nox5 is expressed in human retina, 15 but is not easily studied in vivo due to its absence from the mouse and rat genome, albeit Nox5 is expressed in other species such as cows and rabbits. 18 Multiple pathways are involved in the increase in Nox and ROS levels that occur in hypertension and diabetes including the renin-angiotensin system, sheer stress on blood vessels, the hyperglycaemic-induction of metabolic pathways and inflammation. 10 19, 20 21 However, treatment strategies to block the excess production of ROS derived from Nox have until recently been hindered by the absence of agents that inhibit specific Nox isoforms.…”

On the Clinical Pharmacology of Reactive Oxygen Species

“…NOX isoforms also differ regarding ROS generation kinetics (low and high output), abundance (low and high expression levels), subunit requirements, and modes of activation (basally active or inactive). Concerning regulation, NOX5 and the DUOXs stand out by being directly calcium-activated (Rigutto et al, 2009;Touyz et al, 2019b). However, unlike NOX5, DUOX produces H 2 O 2 similar to NOX4; for details, see (Altenhöfer et al, 2015).…”

NOX5 is Expressed Aberrantly but Not a Critical Pathogenetic Gene in Hirschsprung Disease

“…NOX5 was rst reported in 2001 based on a blast search using the C-terminus of gp91 phox as bait to identify novel transcripts (23). The exact pathophysiological signi cance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyper activation has been implicated in cardiovascular disease, kidney injury and cancer (24). One of the distinguishing features about NOX5 is its dependence on Ca 2+ for its regulation (23).…”