Cholinergic signaling impairs cardiomyocyte cohesion

Yeruva, Sunil ; Körber, Lars; Hiermaier, Matthias; Egu, Desalegn T.; Kempf, Ellen und Waschke, Jens (2022): Cholinergic signaling impairs cardiomyocyte cohesion. In: Acta Physiologica, Bd. 236, Nr. 3

Abstract

Aim: Cardiac autonomic nervous system (ANS) dysregulation is a hallmark of several cardiovascular diseases. Adrenergic signaling enhanced cardiomyocyte cohesion via PKA-mediated plakoglobin phosphorylation at serine 665, referred to as positive adhesiotropy. This study investigated cholinergic regulation of cardiomyocyte cohesion using muscarinic receptor agonist carbachol (CCH). Methods: Dissociation assays, Western blot analysis, immunostaining, atomic force microscopy (AFM), immunoprecipitation, transmission electron microscopy (TEM), triton assays, and siRNA knockdown of genes were performed in either HL-1 cells or plakoglobin (PG) wild type (Jup(+/+)) and knockout (Jup(-/-)) mice, which served as a model for arrhythmogcnic cardiomyopathy. Results: In HL-1 cells grown in norepinephrine (NE)-containing medium for baseline adrenergic stimulation, and mu rine cardiac slice cultures from Jup(+/+) and Jup(-/-) mice CCH treatment impaired cardiomyocyte cohesion. I m mu nostainings and AFM experiments revealed that CCH reduced desmoglein 2 (DSG2) localization and binding at cell borders. Furthermore, CCH reduced intercalated disc plaque thickness in both Jup(+/+) and Jup(-/- )mice, evidenced by TEM analysis. immunoprecipitation experiments in HL-1 cells revealed no changes in DSG2 interaction with desmoplakin (DP), plakophilin 2 (PKP2), PG, and desmin (DES) after CCH treatment. However, knockdown of any of the above proteins abolished CCH-mediated loss of cardiomyocyte cohesion. Furthermore, in HL-1 cells, CCH inhibited adrenergic-stimulated ERK phosphorylation but not PG phosphorylation at serine 665. In addition, CCH activated the AKT/GSK-3 beta axis in the presence of NE. Conclusion: Our results demonstrate that cholinergic signaling antagonizes the positive effect of adrenergic signaling on cardiomyocyte cohesion and thus causes negative adhesiotropy independent of PG phosphorylation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1748-1708
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892