NADPH oxidase 4 and its role in the cardiovascular system

The heart relies on complex mechanisms that provide adequate myocardial oxygen supply in order to maintain its contractile function. At the cellular level, oxygen undergoes one electron reduction to superoxide through the action of different types of oxidases (e.g. xanthine oxidases, uncoupled nitric oxide synthases, NADPH oxidases or NOX). Locally generated oxygen-derived reactive species (ROS) are involved in various signaling pathways including cardiac adaptation to different types of physiological and pathophysiological stresses (e.g. hypoxia or overload). The specific effects of ROS and their regulation by oxidases are dependent on the amount of ROS generated and their specific subcellular localization. The NOX family of NADPH oxidases is a main source of ROS in the heart. Seven distinct Nox isoforms (NOX1–NOX5 and DUOX1 and 2) have been identified, of which NOX1, 2, 4 and 5 have been characterized in the cardiovascular system. For the purposes of this review, we will focus on the effects of NADPH oxidase 4 (NOX4) in the heart.

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The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidases

Biochemical Journal ◽

10.1042/bj20082182 ◽

2009 ◽

Vol 422 (2) ◽

pp. 373-382 ◽

Cited By ~ 23

Author(s):

Kei Miyano ◽

Hirofumi Koga ◽

Reiko Minakami ◽

Hideki Sumimoto

Keyword(s):

Amino Acids ◽

Nadph Oxidase ◽

Essential Role ◽

Cellular Level ◽

Nadph Oxidases ◽

Catalytic Core ◽

Rac Gtpases ◽

Nadph Oxidase 1 ◽

Nox Family ◽

Insert Region

Rac1 and Rac2, which belong to the Rho subfamily of Ras-related GTPases, play an essential role in activation of gp91phox/Nox2 (cytochrome b-245, β polypeptide; also known as Cybb), the catalytic core of the superoxide-producing NADPH oxidase in phagocytes. Rac1 also contributes to activation of the non-phagocytic oxidases Nox1 (NADPH oxidase 1) and Nox3 (NADPH oxidase 3), each related closely to gp91phox/Nox2. It has remained controversial whether the insert region of Rac (amino acids 123–135), unique to the Rho subfamily proteins, is involved in gp91phox/Nox2 activation. In the present study we show that removal of the insert region from Rac1 neither affects activation of gp91phox/Nox2, which is reconstituted under cell-free and whole-cell conditions, nor blocks its localization to phagosomes during ingestion of IgG-coated beads by macrophage-like RAW264.7 cells. The insert region of Rac2 is also dispensable for gp91phox/Nox2 activation at the cellular level. Although Rac2, as well as Rac1, is capable of enhancing superoxide production by Nox1 and Nox3, the enhancements by the two GTPases are both independent of the insert region. We also demonstrate that Rac3, a third member of the Rac family in mammals, has an ability to activate the three oxidases and that the activation does not require the insert region. Thus the insert region of the Rac GTPases does not participate in regulation of the Nox family NADPH oxidases.

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Abstract 174: Roles of Pericyte NADPH Oxidase 4 in Acute Brain Ischemia

Stroke ◽

10.1161/str.45.suppl_1.174 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Ataru Nishimura ◽

Tetsuro Ago ◽

Masaki Tachibana ◽

Noriko Makihara ◽

Ryu Matsuo ◽

...

Keyword(s):

Nadph Oxidase ◽

Brain Ischemia ◽

Infarct Volume ◽

Neurovascular Unit ◽

Double Labeling ◽

Nadph Oxidase 4 ◽

Brain Pericytes ◽

Acute Brain Ischemia ◽

Nox Family ◽

The Brain

Pericytes exist abundantly in the brain and compose the neurovascular unit. It has been elucidated that pericytes play a key role in the formation and maintenance of the blood-brain barrier (BBB), thus being considered to play significant roles in brain ischemia. The NADPH oxidase (Nox) family proteins are a major source of reactive oxygen species (ROS). We have reported previously that Nox4 is abundantly expressed in pericytes among the Nox family. Our goal was to elucidate the roles of Nox4 in brain pericytes during acute brain ischemia. We confirmed by quantitative PCR that Nox4 was abundantly expressed in human cultured brain microvascular pericytes (HBMPC) and was significantly upregulated by hypoxia. We produced a mouse middle cerebral artery occlusion (MCAO) stroke model and examined the expression of Nox4 in the brain. Immunofluorescent double labeling demonstrated that Nox4 expression was upregulated in microvessels particularly in peri-infarct areas and was co-stained with PDGFRβ, a pericyte marker. In order to elucidate the role of Nox4 in brain pericyte during brain ischemia, we generated mice with human Nox4 overexpression using a promoter of SM22α, a pericyte/smooth muscle cell marker (Tg-Nox4). We confirmed that SM22α was expressed in mouse brain pericytes by co-immunostaining with PDGFRβ. We isolated microvessels from Tg-Nox4 brain and confirmed that human Nox4 mRNA was highly expressed. In MCAO model, the infarct volume was significantly larger in Tg-Nox4 than in littermate controls. Confocal microscopy demonstrated that IgG leakage in peri-infarct areas was significantly increased in Tg-Nox4, suggesting that Nox4 overexpression in pericytes enhanced BBB breakdown during acute brain ischemia. To elucidate the mechanisms, we induced adenovirus-mediated overexpression of Nox4 in HBMPC. We demonstrated that Nox4 overexpression increased NFκB phosphorylation and MMP9 expression in the cells.In conclusion, Nox4 may be a major source of ROS in brain pericytes and is upregulated directly by hypoxia in peri-infarct areas during acute brain ischemia. Pericyte Nox4 may enhance BBB breakdown through the activation of NFκB-MMP9 signaling during acute brain ischemia.

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Physiological Reviews ◽

10.1152/physrev.00044.2005 ◽

2007 ◽

Vol 87 (1) ◽

pp. 245-313 ◽

Cited By ~ 3856

Author(s):

Karen Bedard ◽

Karl-Heinz Krause

Keyword(s):

Nadph Oxidase ◽

Regulation Of Gene Expression ◽

Nadph Oxidases ◽

Phagocyte Nadph Oxidase ◽

Current State ◽

Wide Range ◽

The Family ◽

Activation Mechanisms ◽

Long Time ◽

Nox Family

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX actvity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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Clarity on the Isoform-Specific Roles of NADPH Oxidases and NADPH Oxidase-4 in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.116.307096 ◽

2016 ◽

Vol 36 (4) ◽

pp. 579-581 ◽

Cited By ~ 18

Author(s):

David J.R. Fulton ◽

Scott A. Barman

Keyword(s):

Nadph Oxidase ◽

Nadph Oxidases ◽

Nadph Oxidase 4

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Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise

eLife ◽

10.7554/elife.41044 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 15

Author(s):

Matthew Hancock ◽

Anne D Hafstad ◽

Adam A Nabeebaccus ◽

Norman Catibog ◽

Angela Logan ◽

...

Keyword(s):

Nadph Oxidase ◽

Exercise Capacity ◽

Exercise Performance ◽

Acute Exercise ◽

Contractile Function ◽

Beneficial Effects ◽

Nadph Oxidase 4 ◽

Endogenous Antioxidants ◽

Exercise Induced ◽

Nrf2 Activator

Regular exercise has widespread health benefits. Fundamental to these beneficial effects is the ability of the heart to intermittently and substantially increase its performance without incurring damage, but the underlying homeostatic mechanisms are unclear. We identify the ROS-generating NADPH oxidase-4 (Nox4) as an essential regulator of exercise performance in mice. Myocardial Nox4 levels increase during acute exercise and trigger activation of the transcription factor Nrf2, with the induction of multiple endogenous antioxidants. Cardiomyocyte-specific Nox4-deficient (csNox4KO) mice display a loss of exercise-induced Nrf2 activation, cardiac oxidative stress and reduced exercise performance. Cardiomyocyte-specific Nrf2-deficient (csNrf2KO) mice exhibit similar compromised exercise capacity, with mitochondrial and cardiac dysfunction. Supplementation with an Nrf2 activator or a mitochondria-targeted antioxidant effectively restores cardiac performance and exercise capacity in csNox4KO and csNrf2KO mice respectively. The Nox4/Nrf2 axis therefore drives a hormetic response that is required for optimal cardiac mitochondrial and contractile function during physiological exercise.

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Ammoniak induziert NADPH-Oxidase 4- vermittelt oxidativen Stress in kultivierten Rattenastrozyten

Zeitschrift für Gastroenterologie ◽

10.1055/s-0035-1568024 ◽

2015 ◽

Vol 53 (12) ◽

Author(s):

A Karababa ◽

S Aygul ◽

B Görg ◽

D Häussinger

Keyword(s):

Nadph Oxidase ◽

Nadph Oxidase 4

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Faculty Opinions recommendation of NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717961096.793467965 ◽

2012 ◽

Author(s):

Ines Armando

Keyword(s):

Nadph Oxidase ◽

Renal Injury ◽

Kidney Fibrosis ◽

Nadph Oxidase 4

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Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner

Clinical Epigenetics ◽

10.1186/s13148-021-01016-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Hongzhen Li ◽

Chunyan Peng ◽

Chenhui Zhu ◽

Shuang Nie ◽

Xuetian Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nadph Oxidase ◽

Western Blot ◽

Cancer Progression ◽

Histone Methylation ◽

Invasion And Metastasis ◽

Independent Manner ◽

Nadph Oxidase 4

Abstract Background Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. Methods A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. Results We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. Conclusions This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

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Monoclonal Antibodies as Neurological Therapeutics

Pharmaceuticals ◽

10.3390/ph14020092 ◽

2021 ◽

Vol 14 (2) ◽

pp. 92

Author(s):

Panagiotis Gklinos ◽

Miranta Papadopoulou ◽

Vid Stanulovic ◽

Dimos D. Mitsikostas ◽

Dimitrios Papadopoulos

Keyword(s):

Monoclonal Antibodies ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Therapeutic Agents ◽

Medical Specialties ◽

Specific Effects ◽

Different Types ◽

Neurological Conditions ◽

Disease Pathways

Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease.

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