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Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin

Maria Shoykhet1, Sebastian Trenz1, Ellen Kempf1

  • 1Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.

JCI Insight
|August 26, 2020
PubMed

Insights

Stabilizing cardiomyocyte adhesion, crucial for preventing arrhythmogenic cardiomyopathy (AC), can be achieved through various signaling pathways. These pathways enhance cell adhesion, offering new therapeutic targets for heart disease.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cell Adhesion Mechanisms

Background:

  • Arrhythmogenic cardiomyopathy (AC) is a heart disease linked to mutations in desmosomal proteins like desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP).
  • Current AC therapies manage symptoms and arrhythmias, as the precise mechanisms of desmosomal proteins in cardiomyocyte function remain unclear.
  • Stabilizing desmosomal cardiomyocyte adhesion and hyperadhesion presents a novel therapeutic strategy, potentially making adhesion independent of calcium (Ca2+).

Purpose of the Study:

  • To elucidate the signaling pathways that regulate cardiomyocyte adhesion under basal and hyperadhesive conditions.
  • To investigate the role of adrenergic signaling, protein kinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase 1/2 (ERK1/2) in controlling cell adhesion.
  • To examine the impact of plakoglobin (PG) deficiency on these adhesion-regulating mechanisms in the context of AC.

Main Methods:

  • Utilized dissociation assays in HL-1 cells and murine ventricular cardiac slice cultures to study cardiomyocyte adhesion.
  • Investigated the effects of adrenergic signaling, PKC activation, p38MAPK inhibition, and ERK1/2 activation on cell adhesion.
  • Analyzed the recruitment of DSG2 to cell junctions and PG phosphorylation at S665.
  • Compared adhesion responses in wild-type and PG-deficient mice with an AC phenotype.

Main Results:

  • Adrenergic signaling, PKC activation, and p38MAPK inhibition enhanced cardiomyocyte adhesion (positive adhesiotropy) and induced hyperadhesion.
  • ERK1/2 activation correlated with positive adhesiotropy.
  • Adrenergic signaling promoted PG phosphorylation at S665 under both basal and hyperadhesive states.
  • Adrenergic signaling and p38MAPK inhibition led to increased DSG2 at cell junctions.
  • In PG-deficient mice, only PKC activation and p38MAPK inhibition effectively enhanced cardiomyocyte adhesion.

Conclusions:

  • Cardiomyocyte adhesion can be modulated and stabilized through distinct signaling pathways.
  • These findings highlight potential therapeutic targets for stabilizing desmosomal junctions in AC.
  • The efficacy of certain signaling mechanisms in enhancing adhesion is partially dependent on the presence of PG, as observed in AC models.

Keywords:
ArrhythmiasCardiologyCardiovascular diseaseCell migration/adhesion

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