NADPH oxidase 4 as a source of hydrogen peroxide can regulate norepinephrine levels and vascular contraction
4 affiliations
- 1Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus at TUD Dresden University of Technology , ,
- 2Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Faculty of Medicine and University Hospital Carl Gustav Carus at TUD Dresden University of Technology , ,
- 3Department of Internal Medicine and Cardiology, Heart Center Dresden - Laboratory of Experimental and Molecular Cardiology, Technische Universität Dresden , ,
- 4Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus at TUD Dresden University of Technology , ,
Abstract
Introduction: The adrenal glands play a pivotal role in maintaining physiological homeostasis, and disturbance in their function can lead to significant clinical disorders, including hypertension, and adrenal insufficiency. Reactive oxygen species (ROS), once considered merely byproducts of cellular metabolism, are now recognized as critical signaling molecules within the adrenal cortex and medulla. Among the major enzymatic sources of ROS are NADPH oxidases (Nox). Dysregulation of Nox-derived ROS has been linked to altered steroidogenesis, oxidative stress- mediated adrenal damage, and tumorigenic processes. We aimed to elucidate the role of Nox4 on adrenal function under healthy conditions.
Methods: Using Nox4-knockout mouse model, adrenal effects were assessed by histological analysis, real-time PCR, and cathecholamine quantification using HPLC-ECD and LC-MS/MS. Cardiovascular function was evaluated by echocardiography, blood pressure measurements, and ex vivo vascular function analysis.
Results: Here, we demonstrated that Nox4 is expressed in the mouse adrenal gland, and its deletion led to decreased hydrogen peroxide production, diminished dopamine beta-hydroxylase mRNA expression, and reduced norepinephrine levels. In chromaffin cells, treatment with hydrogen peroxide stimulated catecholamine release and increased dopamine beta-hydroxylase expression, indicating a regulatory role of hydrogen peroxide in catecholamine synthesis and secretion. Further analysis of the physiological consequences of reduced norepinephrine levels in Nox4 −/− mice revealed decreased alpha-1 adrenergic receptor expression and impaired adrenergic vascular contraction, while cardiac function remained unaffected. In a model of physical activity, Nox4 depletion resulted in smaller adrenal glands and lower urinary norepinephrine concentrations, further explaining diminished physical activity of Nox4 −/− mice.
Conclusion: Our findings provide evidence that Nox4-derived H ₂ O ₂ plays a role in norepinephrine release and norepinephrine-mediated functions. Hence, loss of Nox4 impairs vascular contractility and reduces physical activity performance, highlighting the physiological importance of Nox4 in adrenal function.
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BibTeX
@article{brendel2026nadph,
title = {{NADPH oxidase 4 as a source of hydrogen peroxide can regulate norepinephrine levels and vascular contraction}},
author = {Heike Brendel and Jennifer Mittag and Nicole Bechmann and Amna Shahid Mehmood-Ashraf and Antje Schauer and Patrick Diaba-Nuhoho and Mirko Peitzsch and Graeme Eisenhofer and Stefan R. Bornstein and Henning Morawietz and Coy Brunssen},
journal = {Frontiers in endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1932927},
url = {https://europepmc.org/article/PMC/PMC13671950},
note = {CC BY},
}
RIS
TY - JOUR
TI - NADPH oxidase 4 as a source of hydrogen peroxide can regulate norepinephrine levels and vascular contraction
AU - Heike Brendel
AU - Jennifer Mittag
AU - Nicole Bechmann
AU - Amna Shahid Mehmood-Ashraf
AU - Antje Schauer
AU - Patrick Diaba-Nuhoho
AU - Mirko Peitzsch
AU - Graeme Eisenhofer
AU - Stefan R. Bornstein
AU - Henning Morawietz
AU - Coy Brunssen
PY - 2026
DA - 2026/10/02
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1932927
UR - https://europepmc.org/article/PMC/PMC13671950
AB - Introduction: The adrenal glands play a pivotal role in maintaining physiological homeostasis, and disturbance in their function can lead to significant clinical disorders, including hypertension, and adrenal insufficiency. Reactive oxygen species (ROS), once considered merely byproducts of cellular metabolism, are now recognized as critical signaling molecules within the adrenal cortex and medulla. Among the major enzymatic sources of ROS are NADPH oxidases (Nox). Dysregulation of Nox-derived ROS has been linked to altered steroidogenesis, oxidative stress- mediated adrenal damage, and tumorigenic processes. We aimed to elucidate the role of Nox4 on adrenal function under healthy conditions. Methods: Using Nox4-knockout mouse model, adrenal effects were assessed by histological analysis, real-time PCR, and cathecholamine quantification using HPLC-ECD and LC-MS/MS. Cardiovascular function was evaluated by echocardiography, blood pressure measurements, and ex vivo vascular function analysis. Results: Here, we demonstrated that Nox4 is expressed in the mouse adrenal gland, and its deletion led to decreased hydrogen peroxide production, diminished dopamine beta-hydroxylase mRNA expression, and reduced norepinephrine levels. In chromaffin cells, treatment with hydrogen peroxide stimulated catecholamine release and increased dopamine beta-hydroxylase expression, indicating a regulatory role of hydrogen peroxide in catecholamine synthesis and secretion. Further analysis of the physiological consequences of reduced norepinephrine levels in Nox4 −/− mice revealed decreased alpha-1 adrenergic receptor expression and impaired adrenergic vascular contraction, while cardiac function remained unaffected. In a model of physical activity, Nox4 depletion resulted in smaller adrenal glands and lower urinary norepinephrine concentrations, further explaining diminished physical activity of Nox4 −/− mice. Conclusion: Our findings provide evidence that Nox4-derived H ₂ O ₂ plays a role in norepinephrine release and norepinephrine-mediated functions. Hence, loss of Nox4 impairs vascular contractility and reduces physical activity performance, highlighting the physiological importance of Nox4 in adrenal function.
SN - 1664-2392
ER -