In:
Acta Physiologica, Wiley, Vol. 236, No. 3 ( 2022-11)
Abstract:
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 arrhythmogenic cardiomyopathy. Results In HL‐1 cells grown in norepinephrine (NE)‐containing medium for baseline adrenergic stimulation, and murine cardiac slice cultures from Jup +/+ and Jup −/− mice CCH treatment impaired cardiomyocyte cohesion. Immunostainings 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‐3β 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.
Type of Medium:
Online Resource
ISSN:
1748-1708
,
1748-1716
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2617148-X
detail.hit.zdb_id:
2219379-0
SSG:
12
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