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      NOX5: Molecular biology and pathophysiology

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          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 biology to human disease, and highlights the unique characteristics of this enigmatic Nox isoform.

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          Most cited references106

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          Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system.

          The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.
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            Oxidative Stress, Inflammation, and Vascular Aging in Hypertension.

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              Cell transformation by the superoxide-generating oxidase Mox1.

              Reactive oxygen species (ROS) generated in some non-phagocytic cells are implicated in mitogenic signalling and cancer. Many cancer cells show increased production of ROS, and normal cells exposed to hydrogen peroxide or superoxide show increased proliferation and express growth-related genes. ROS are generated in response to growth factors, and may affect cell growth, for example in vascular smooth-muscle cells. Increased ROS in Ras-transformed fibroblasts correlates with increased mitogenic rate. Here we describe the cloning of mox1, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes, gp91phox. mox1 messenger RNA is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes. In smooth-muscle cells, platelet-derived growth factor induces mox1 mRNA production, while antisense mox1 mRNA decreases superoxide generation and serum-stimulated growth. Overexpression of mox1 in NIH3T3 cells increases superoxide generation and cell growth. Cells expressing mox1 have a transformed appearance, show anchorage-independent growth and produce tumours in athymic mice. These data link ROS production by Mox1 to growth control in non-phagocytic cells.
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                Author and article information

                Contributors
                rhian.touyz@glasgow.ac.uk
                Journal
                Exp Physiol
                Exp. Physiol
                10.1111/(ISSN)1469-445X
                EPH
                expphysiol
                Experimental Physiology
                John Wiley and Sons Inc. (Hoboken )
                0958-0670
                1469-445X
                18 March 2019
                01 May 2019
                : 104
                : 5 ( doiID: 10.1113/eph.2019.104.issue-5 )
                : 605-616
                Affiliations
                [ 1 ] Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Centre University of Glasgow Glasgow UK
                Author notes
                [*] [* ] Correspondence

                Rhian M. Touyz, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.

                Email: rhian.touyz@ 123456glasgow.ac.uk

                [†]

                Recipient of the 2017 Joan Mott Award, Physiological Society, awarded at the 2017 IUPS meeting, Rio de Janeiro, Brazil.

                Author information
                https://orcid.org/0000-0003-0670-0887
                Article
                EPH12465
                10.1113/EP086204
                6519284
                30801870
                2a76b4b0-4028-434f-8f31-dfe0fc609ba8
                © 2019 The Authors. Experimental Physiology Published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 January 2019
                : 20 February 2019
                Page count
                Figures: 5, Tables: 1, Pages: 12, Words: 10153
                Funding
                Funded by: British Heart Foundation
                Award ID: RG/13/7/30099
                Award ID: RE/13/5/30177
                Award ID: MC‐PC‐15076
                Award ID: CH/12/29762
                Categories
                Lecture
                Lecture
                Custom metadata
                2.0
                eph12465
                1 May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:15.05.2019

                Anatomy & Physiology
                cancer,cardiovascular disease,kidney disease,nox isoforms,oxidative stress,reactive oxygen species

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