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. 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 Ca2+, 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 biology to human disease, and highlights the unique characteristics of this enigmatic Nox isoform.
Highlights
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are a family of transmembrane proteins that transfer electrons across membranes
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
We demonstrated that NOX5 regulates vascular contraction in NOX5-expressing mice and that it is essential for smooth muscle contraction in arthropod models (Montezano et al, 2018), supporting earlier studies in Drosophila (Ritsick, Edens, Finnerty, & Lambeth, 2007)
Summary
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are a family of transmembrane proteins that transfer electrons across membranes. In an NADPH-dependent manner, Noxs catalyse the reduction of O2 to produce superoxide (O2−) (NADPH + 2O2 → NADP+ + H+ + 2O2−), which in turn dismutates to generate hydrogen peroxide [H2O2; spontaneously or catalysed by superoxide dismutase (SOD); Bedard & Krause, 2007; Maghzal, Krause, Stocker, & Jaquet, 2012]. This cascade of reactions leads to generation of secondary reactive oxygen species (ROS), including the reaction of O2− with nitric oxide (NO) to form peroxynitrite, the iron-catalysed Fenton reaction to produce hydroxyl radical (OH−), and peroxidase-catalysed generation of hypochlorous acid (HOCl; Maghzal et al, 2012). To contextualise NOX5 within the Nox family, we provide a brief overview of Nox functions and Nox isoforms
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