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NADPH oxidase-dependent reactive oxygen species upregulate KCa3.1 to promote atrial fibroblast activation.

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Τίτλος: NADPH oxidase-dependent reactive oxygen species upregulate KCa3.1 to promote atrial fibroblast activation.
Συγγραφείς: Wu J; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Zhu Y; Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China., Wu Y; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Liu X; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Jiang W; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Wang Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China., Wang Z; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Li M; Institute of Biology and Medical Sciences, Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Liu L; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China., Zhao J; Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou, 225001, China. Electronic address: zhaojinghmu@163.com., Zhao L; Department of Pathology and Pathophysiology, School of Basic Medical Science, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou, Jiangsu, 215123, China. Electronic address: lmzhao@suda.edu.cn.
Πηγή: Experimental cell research [Exp Cell Res] 2026 Aug 01; Vol. 461 (1), pp. 115105. Date of Electronic Publication: 2026 Jun 15.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Academic Press Country of Publication: United States NLM ID: 0373226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2422 (Electronic) Linking ISSN: 00144827 NLM ISO Abbreviation: Exp Cell Res Subsets: MEDLINE
Imprint Name(s): Publication: Orlando Fl : Academic Press
Original Publication: New York, Academic Press.
Ιατρικοί όροι (MeSH): Reactive Oxygen Species*/metabolism , Fibroblasts*/metabolism , Fibroblasts*/drug effects , Intermediate-Conductance Calcium-Activated Potassium Channels*/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels*/genetics , NADPH Oxidases*/metabolism , Heart Atria*/metabolism , Heart Atria*/pathology , Heart Atria*/cytology, Up-Regulation/drug effects ; Angiotensin II/pharmacology ; NADPH Oxidase 4/metabolism ; NADPH Oxidase 4/genetics ; Hydrogen Peroxide/pharmacology ; NADPH Oxidase 2/metabolism ; NADPH Oxidase 2/genetics ; Animals ; Rats ; Cells, Cultured ; Rats, Sprague-Dawley ; Male ; Cell Movement ; Cell Proliferation
Περίληψη: Atrial fibroblast activation is a central cellular event driving atrial fibrotic remodeling, which plays a critical role in the initiation and maintenance of atrial fibrillation (AF). Our previous studies have identified the intermediate-conductance Ca2+-activated potassium channel KCa3.1 as a key mediator of reactive atrial fibrosis. However, the upstream mechanisms regulating its expression under pro-fibrotic stimulation remain incompletely defined. The present study aimed to investigate whether NADPH oxidase (NOX)-derived reactive oxygen species (ROS) regulate KCa3.1 expression and function in atrial fibroblasts. Primary rat atrial fibroblasts were stimulated with angiotensin II (Ang II). Ang II markedly increased intracellular ROS generation through AT1 receptor-dependent activation of NOX. Pharmacological inhibition with Diphenyleneiodonium (DPI) or CRISPR-mediated deletion of NOX2 or NOX4 significantly suppressed Ang II-induced upregulation of KCa3.1 expression and channel activity. Exposure to hydrogen peroxide (H2O2) alone was sufficient to enhance KCa3.1 expression and TRAM-34-sensitive currents. Functionally, pharmacological blockade or genetic deletion of KCa3.1 markedly attenuated ROS-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, ROS activated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of either pathway suppressed KCa3.1 promoter activity and expression. Collectively, these findings identify a NOX-ROS-JNK/ERK-KCa3.1 signaling axis that drives atrial fibroblast activation and may represent a potential therapeutic target in oxidative stress-associated atrial remodeling.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Atrial fibroblasts; ERK; Intermediate-conductance Ca(2+)-activated K(+) channels; JNK; NADPH oxidase; Reactive oxygen species
Substance Nomenclature: 0 (Reactive Oxygen Species)
0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
EC 1.6.3.- (NADPH Oxidases)
11128-99-7 (Angiotensin II)
EC 1.6.3.- (NADPH Oxidase 4)
BBX060AN9V (Hydrogen Peroxide)
0 (Kcnn4 protein, rat)
EC 1.6.3.- (NADPH Oxidase 2)
Entry Date(s): Date Created: 20260615 Date Completed: 20260627 Latest Revision: 20260628
Update Code: 20260628
DOI: 10.1016/j.yexcr.2026.115105
PMID: 42297202
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1090-2422
DOI:10.1016/j.yexcr.2026.115105