Plakophilin-2 haploinsuffciency causes calcium handling deficits and modulates the cardiac response towards stress

Chantal J.M. van Opbergen, Maartje Noorman, Anna Pfenniger, Jaël S. Copier, Sarah H. Vermij, Zhen Li, Roel van der Nagel, Mingliang Zhang, Jacques M.T. de Bakker, Aaron M. Glass, Peter J. Mohler, Steven M. Taffet, Marc A. Vos, Harold V.M. van Rijen, Mario Delmar, Toon A.B. van Veen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsuffciency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.

Original languageEnglish (US)
Article number4076
JournalInternational journal of molecular sciences
Issue number17
StatePublished - Sep 1 2019


  • Arrhythmogenic cardiomyopathy
  • Calcium handling
  • Cardiac pressure overload
  • Exercise
  • Fibrosis
  • Inflammation
  • Plakophilin-2
  • Second hit

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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