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  3. Elevated KCa3.1 expression by angiotensin II via the ERK/NF-κB pathway contributes to atrial fibrosis

Elevated KCa3.1 expression by angiotensin II via the ERK/NF-κB pathway contributes to atrial fibrosis

  • J Mol Cell Cardiol. 2025 Mar 21:202:133-143. doi: 10.1016/j.yjmcc.2025.03.009.
Zujuan Wang 1,  Yujie Ren 2,  Dongmei Zhang 1,  Gang She 3,  Yan Wang 3,  Guangyao Li 1,  Xiaodong Sun 1,  Dong Zheng 1,  Zhongjuan Wang 4,  Xiu-Ling Deng 3,  Ying Zhao 5,  Limei Zhao 6
Affiliations

Affiliations

  • 1 Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China.
  • 2 Department of Pathology, Xi'an People's Hospital (Xian Fourth Hospital), 21 Jiefang Road, Xi'an 710004, Shaanxi, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China.
  • 4 Institute of Biology and Medical Sciences, Soochow University, 199 Ren-ai Road, Suzhou 215123, China.
  • 5 Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China. Electronic address: yzhao@suda.edu.cn.
  • 6 Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China. Electronic address: lmzhao@suda.edu.cn.
PMID: 40122157 DOI: 10.1016/j.yjmcc.2025.03.009
Abstract

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia characterized by atrial fibrosis which involves excessed proliferation and increased activity of fibroblast and myofibroblast, as well as alterations in the extracellular matrix (ECM). The specific mechanism driving fibrosis in atrial fibroblasts and myofibroblsats remains incompletely understood. This study investigates the role of the intermediate-conductance CA2+-activated K+ channel (KCA3.1) in Angiotensin II (Ang II)-induced atrial fibrosis and elucidates the underlying mechanisms. Primary rat atrial fibroblasts/myofibroblasts were treated with Ang II to evaluate KCA3.1 expression, cells proliferation and ECM production. The involvement of ERK/NF-κB signaling pathway was assessed using specific inhibitors. Ang II treatment increased KCA3.1 expression, stimulated the proliferation of fibroblasts/myofibroblasts, and enhanced ECM production, effects that were attenuated by the Ang II receptor antagonist Losartan and the KCA3.1 inhibitor TRAM-34. Knockdown of KCA3.1 using siRNA significantly reduced Ang II-induced collagen synthesis, confirming its critical role in fibrosis. The ERK/NF-κB pathway was found to mediate Ang II-induced upregulation of KCA3.1, as evidenced by inhibition with specific inhibitors. In vivo, Ang II infusion in rats increased KCA3.1 expression and atrial fibrosis, with atria showing greater susceptibility to fibrosis compared to ventricle. These effects were mitigated by losartan and TRAM-34. In conclusion, our findings demonstrate that Ang II-induced upregulation of KCA3.1 through ERK/NF-κB pathway activation in atrial fibroblasts/myofibroblasts promotes cellular proliferation and collagen deposition, ultimately contributing to atrial fibrosis. KCA3.1 represents a promising therapeutic target for the treatment of atrial fibrosis in AF.

Keywords

Angiotensin II; Atrial fibrillation; Atrial fibrosis; ERK; Intermediate-conductance Ca(2+)-activated K(+) channels; NF-κB.

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