Plakophilin-2 Haploinsufficiency 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

Research output: Contribution to journalArticleAcademicpeer-review


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
Article number4076
JournalInternational journal of molecular sciences
Issue number17
Publication statusPublished - 21 Aug 2019


  • arrhythmogenic cardiomyopathy
  • calcium handling
  • cardiac pressure overload
  • exercise
  • fibrosis
  • inflammation
  • plakophilin-2
  • second hit


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