van Opbergen, Chantal J M; Noorman, Maartje; Pfenniger, Anna; Copier, Jaël S; Vermij, Sarah H.; Li, Zhen; van der Nagel, Roel; Zhang, Mingliang; de Bakker, Jacques M T; Glass, Aaron M; Mohler, Peter J; Taffet, Steven M; Vos, Marc A; van Rijen, Harold V M; Delmar, Mario; van Veen, Toon A B (2019). Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress. International journal of molecular sciences, 20(17) MDPI 10.3390/ijms20174076
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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 haploinsufficiency 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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Vermij, Sarah Helena |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1661-6596 |
Publisher: |
MDPI |
Language: |
English |
Submitter: |
Kevin Marc Rupp |
Date Deposited: |
31 Jan 2020 08:42 |
Last Modified: |
07 Aug 2024 15:45 |
Publisher DOI: |
10.3390/ijms20174076 |
PubMed ID: |
31438494 |
Uncontrolled Keywords: |
arrhythmogenic cardiomyopathy calcium handling cardiac pressure overload exercise fibrosis inflammation plakophilin-2 second hit |
BORIS DOI: |
10.7892/boris.138171 |
URI: |
https://boris.unibe.ch/id/eprint/138171 |
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