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

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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Author response for "Increased ILC3s associated with higher levels of IL‐1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase"

10.1002/eji.201948141/v2/response1 ◽

2019 ◽

Author(s):

Tzu‐Yi Chan ◽

Chia‐Liang Yen ◽

Ya‐Fang Huang ◽

Pei‐Chi Lo ◽

Peter A. Nigrovic ◽

...

Keyword(s):

Nadph Oxidase ◽

Inflammatory Arthritis ◽

Author Response

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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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Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel by NADPH oxidase 4

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1109546108 ◽

2011 ◽

Vol 108 (38) ◽

pp. 16098-16103 ◽

Cited By ~ 76

Author(s):

Q.-A. Sun ◽

D. T. Hess ◽

L. Nogueira ◽

S. Yong ◽

D. E. Bowles ◽

...

Keyword(s):

Skeletal Muscle ◽

Nadph Oxidase ◽

Ryanodine Receptor ◽

Redox Regulation ◽

Release Channel ◽

Nadph Oxidase 4

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QSYQ Attenuates Oxidative Stress and Apoptosis Induced Heart Remodeling Rats through Different Subtypes of NADPH-Oxidase

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/824960 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Yong Wang ◽

Chun Li ◽

Yuli Ouyang ◽

Tianjiao Shi ◽

Xiaomin Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Nadph Oxidase ◽

Caspase 3 ◽

Ventricular Remodeling ◽

Cardiac Injury ◽

Myocardial Tissue ◽

Therapeutic Effects ◽

Histological Changes ◽

Nadph Oxidase 4

We aim to investigate the therapeutic effects of QSYQ, a drug of heart failure (HF) in clinical practice in China, on a rat heart failure (HF) model. 3 groups were divided: HF model group (LAD ligation), QSYQ group (LAD ligation and treated with QSYQ), and sham-operated group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Rats with HF showed obvious histological changes including necrosis and inflammation foci, elevated ventricular remodeling markers levels(matrix metalloproteinases-2, MMP-2), deregulated ejection fraction (EF) value, increased formation of oxidative stress (Malondialdehyde, MDA), and up-regulated levels of apoptotic cells (caspase-3, p53 and tunnel) in myocardial tissue. Treatment of QSYQ improved cardiac remodeling through counter-acting those events. The improvement of QSYQ was accompanied with a restoration of NADPH oxidase 4 (NOX4) and NADPH oxidase 2 (NOX2) pathways in different patterns. Administration of QSYQ could attenuate LAD-induced HF, and AngII-NOX2-ROS-MMPs pathway seemed to be the critical potential targets for QSYQ to reduce the remodeling. Moreover, NOX4 was another key targets to inhibit the p53 and Caspase3, thus to reduce the hypertrophy and apoptosis, and eventually provide a synergetic cardiac protective effect.

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