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Remodeling of KCa2 channels and their effects on mitochondrial metabolism in atrial cardiomyocytes

https://doi.org/10.1007/s00392-025-02625-4

Julia Pfeiffer (Heidelberg)1, C. Richter (Heidelberg)1, C. Heß (Heidelberg)1, J. Hackbarth (Heidelberg)1, H. Gampp (Heidelberg)1, F. Petersenn (Heidelberg)1, M. E. Müller (Heidelberg)1, C. Mages (Heidelberg)1, P. Syren (Heidelberg)1, D. Pijnappels (Leiden)2, A. de Vries (Leiden)2, P. Most (Heidelberg)3, T. Korff (Heidelberg)4, J. Heijman (Maastricht)5, G. Poschet (Heidelberg)6, D. Thomas (Heidelberg)1, P. Lugenbiel (Heidelberg)1, N. Frey (Heidelberg)1, A.-K. Rahm (Heidelberg)1

1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 2Leiden University Medical Center Leiden, Niederlande; 3Universitätsklinikum Heidelberg Innere Medizin III, Inst. für Molekulare und Translationale Kardiologie Heidelberg, Deutschland; 4Universitätsklinikum Heidelberg Institut für Physiologie und Pathophysiologie Heidelberg, Deutschland; 5Maastricht University Cardiovascular Research Institute Maastricht, Niederlande; 6Universität Heidelberg Centre for Organismal Studies Heidelberg, Deutschland

 

Aim: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge. Small-conductance, calcium-activated K+ (KCa2, SK, KCNN) channels contribute to cardiac action potential repolarization and are present in inner mitochondrial membranes of cardiomyocytes. The channels have been implicated in AF susceptibility and constitute promising therapeutic targets. The mechanistic impact of triggers of arrhythmia on atrial mitochondrial KCa2 channels is not known. We hypothesized that tachycardia, β-adrenergic stimulation, and hypoxia differentially affect KCa2.1–2.3 channel remodeling in atrial mitochondria.  

Methods: Inducible atrial cardiomyocytes (iAM) were subjected to proarrhythmic triggers to investigate effects on KCNN mRNA and KCa2 channel protein expression (western blot, WB) and on channel distribution in mitochondria (immunofluorescence staining, IF). Mitochondrial function was assessed with JC-1 staining and seahorse assays.

Results: Hypoxia (1% O2, 24 hours) led to an increased expression of Kcnn1 (p=0.003) and KCa2.1 (p=0.014 in WB and p=0.009 in IF), Kcnn2 (p=0.023), as well as Kcnn3 (p<0.001) and KCa2.3 (p=0.035, WB). β-adrenergic stimulation (1µM Isoproterenol, 24 hours) was linked to a lower expression of Kcnn1 (p<0,001), Kcnn2 (p<0,001) as well as Kcnn3 (p=0.012) and KCa2.3 (p=0.003, WB). Tachypaced cells (5 Hz, 6 hours) showed a decreased expression of Kcnn1 (p=0.004) and KCa2.1 (p<0.001, IF) as well as Kcnn2 (p=0.013) and Kcnn3 (p<0.001). Next, mitochondrial expression of KCa2.1-2.3 protein was confirmed. Selective inhibition of KCa2 channels by apamin resulted in significantly increased basal respiration, maximal respiration, ATP production and spare respiratory capacity.

Conclusion: Subtype-specific KCa2 channel remodeling was induced by tachypacing, β-adrenergic stimulation, or hypoxia, and is expected to differentially determine atrial proarrhythmic remodeling. Selective block of KCa2 channels enhanced mitochondrial respiration. A dual, KCa2-dependent mechanism is revealed: stressor-dependent KCa2 regulation in atrial myocytes impacts both cardiac electrophysiology and cellular metabolism, providing novel options for mechanism-based antiarrhythmic therapy.  

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