Exercise Training Increases the Contribution of NADPH Oxidase 4 to Endothelium‐Dependent Dilation in Collateral‐Dependent Coronary Arterioles

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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NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m116.752261 ◽

2017 ◽

Vol 292 (7) ◽

pp. 3029-3038 ◽

Cited By ~ 45

Author(s):

Karen Bernard ◽

Naomi J. Logsdon ◽

Veronica Miguel ◽

Gloria A. Benavides ◽

Jianhua Zhang ◽

...

Keyword(s):

Nadph Oxidase ◽

Mitochondrial Biogenesis ◽

Lung Fibroblasts ◽

Nuclear Factor ◽

Nadph Oxidase 4 ◽

Dependent Pathway

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NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase

Antioxidants and Redox Signaling ◽

10.1089/ars.2018.7548 ◽

2019 ◽

Vol 31 (1) ◽

pp. 39-58 ◽

Cited By ~ 4

Author(s):

Mark D. Stevenson ◽

Chandrika Canugovi ◽

Aleksandr E. Vendrov ◽

Takayuki Hayami ◽

Dawn E. Bowles ◽

...

Keyword(s):

Heart Failure ◽

Nadph Oxidase ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Ischemic Heart ◽

Ischemic Heart Failure ◽

Nadph Oxidase 4

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Combination of Exercise Training and SOD Mimetic Tempol Enhances Upregulation of Nitric Oxide Synthase in the Kidney of Spontaneously Hypertensive Rats

International Journal of Hypertension ◽

10.1155/2020/2142740 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Pengyu Cao ◽

Osamu Ito ◽

Daisuke Ito ◽

Rong Rong ◽

Yang Zheng ◽

...

Keyword(s):

Nitric Oxide ◽

Exercise Training ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Sod Activity ◽

Spontaneously Hypertensive ◽

Nadph Oxidase Activity ◽

Expression Levels

Both exercise training (Ex) and superoxide dismutase (SOD) mimetic tempol have antihypertensive and renal protective effects in rodent models of several hypertensions. We recently reported that Ex increases nitric oxide (NO) production and the expression levels of endothelial and neuronal NO synthase (eNOS and nNOS) in the kidney and aorta of the spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto rats (WKY). We also found that endogenous hydrogen peroxide (H2O2) upregulates the expression levels of eNOS and nNOS in SHR. To elucidate the mechanism of the Ex-upregulated NO system in the kidney, we examined the additive effect of Ex and tempol on the renal NO system in SHR and WKY. Our data showed that, in SHR, both Ex and tempol increase the levels of H2O2 and nitrate/nitrite (NOx) in plasma and urine. We also observed an increased renal NOS activity and upregulated expression levels of eNOS and nNOS with decreased NADPH oxidase activity. The effects of the combination of Ex and tempol on these variables were cumulate in SHR. On the other hand, we found that Ex increases these variables with increased renal NADPH oxidase activity, but tempol did not change these variables or affect the Ex-induced upregulation in the activity and expression of NOS in WKY. The SOD activity in the kidney and aorta was activated by tempol only in SHR, but not in WKY; whereas Ex increased SOD activity only in the aorta in both SHR and WKY. These results indicate that Ex-induced endogenous H2O2 produced in the blood vessel and other organs outside of the kidney may be carried to the kidney by blood flow and stimulates the NO system in the kidney.

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