Location: Exhibit/Poster Hall A-B - Pennsylvania Convention Center
Poster Board Number: D62
Sunil Yeruva (Ludwig Maximilian University Munich), Lars Körber (Ludwig Maximilian University Munich), Matthias Hiermaier (Ludwig Maximilian University Munich), Desalegn Egu (Ludwig Maximilian University Munich), Ellen Kempf (Ludwig Maximilian University Munich), Jens waschke (Ludwig Maximilian University Munich)
Presenting Author Ludwig Maximilian University Munich
Cardiac autonomic nervous system (ANS) dysregulation is a hallmark of cardiovascular diseases such as heart failure, arrhythmias and myocardial infarction. To understand the role of ANS in cardiomyocyte cohesion, we have previously identified that adrenergic signaling enhances cardiomyocyte cohesion via PKA-mediated plakoglobin phosphorylation at serine 665, which we termed as positive adhesiotropy. In this study, we investigated the role of parasympathetic nervous system in cardiomyocyte cohesion, using carbachol (CCH) as a cholinergic agonist that binds to the muscarinic receptors. Dissociation assays performed in HL-1 cells, grown in norepinephrine (NE) containing medium for baseline adrenergic stimulation, and in murine cardiac slice cultures from wild type (wt) and plakoglobin (Pg) knockout (Jup-/-) mice revealed an impaired cardiomyocyte cohesion after CCH treatment. Electron microscopy revealed that CCH reduced intercalated disc plaque thickness in both wt and Jup-/-mice. Immunostaining and atomic force microscopy in HL-1 cells demonstrated that CCH reduced desmoglein 2 (Dsg2) localization and binding at cell borders. Immunoprecipitation showed no alterations in the interaction of Dsg2, desmoplakin, plakophilin 2 and Pg after CCH treatment. Nevertheless, knockdown of any of the above genes abrogated the loss of cardiomyocyte cohesion in response to CCH. In HL-1 cells, CCH inhibited ERK phosphorylation but not Pg phosphorylation at serine 665 induced by forskolin/rolipram (FR) combination used for adrenergic stimulation. In addition, CCH activated the AKT/GSK-3β axis in the presence of NE. In conclusion, our results demonstrate that cholinergic signaling antagonizes the positive effect of adrenergic signaling on cardiomyocyte cohesion and thus causes negative adhesiotropy, which is independent of Pg phosphorylation.
This work was supported by the Deutsche Forschungsgemeinschaft DFG grant number WA2474/11-1 to Jens Waschke
and by the Friedrich-Baur-Stiftung grant number 01/19 to Sunil Yeruva
