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Interleukin-6 Modulates the Expression and Function of HCN Channels: A Link Between Inflammation and Atrial
Valentina Spinelli1, Annunziatina Laurino1,2, Valentina Balducci1
1Department of Neuroscience, Innovative Treatment, Drug Research and Child Health, University of Firenze, 50139 Firenze, Italy.
International Journal of Molecular Sciences
|November 27, 2024
Summary
Interleukin 6 (IL6) reduces crucial cardiac HCN channels, potentially increasing arrhythmia risk. This study links elevated IL6 to atrial electrical disturbances and heart rhythm problems.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Electrophysiology
Background:
- Inflammatory cytokines like interleukin 6 (IL6) are implicated in cardiac ion channel remodeling.
- Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are vital for cardiac rhythm regulation.
- IL6's specific impact on HCN channels in the atria remains incompletely understood.
Purpose of the Study:
- To investigate the effects of IL6 exposure on HCN channels in cardiac cells and human atrial tissue.
- To explore the potential role of IL6-induced HCN channel alterations in atrial electrical disturbances.
Main Methods:
- Utilized murine atrial HL1 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs).
- Assessed IL6-induced STAT3 phosphorylation and HCN channel (HCN1, HCN2, HCN4) expression.
- Investigated the effect of tocilizumab (an IL6 receptor antagonist) on HCN channels in hiPS-CMs.
- Analyzed IL6 and HCN expression in human atrial biopsies from patients with mitral valve disease.
Main Results:
- IL6 exposure led to STAT3 phosphorylation in both cell models.
- IL6 downregulated HCN1, HCN2, and HCN4 expression in HL1 cells and hiPS-CMs within 24-48 hours.
- Tocilizumab treatment reversed IL6-induced HCN downregulation and normalized action potential frequency in hiPS-CMs.
- Human atrial samples from mitral valve disease patients showed increased IL6 levels and decreased HCN2/HCN4 expression, correlating with atrial size.
Conclusions:
- This study reveals a novel association between elevated IL6 and reduced cardiac HCN channel expression.
- IL6-mediated downregulation of HCN channels may contribute to atrial electrical instability and increased arrhythmia susceptibility.
- These findings highlight a potential mechanism linking inflammation to cardiac rhythm disorders.
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