Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.

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

[img]
Preview
Text
ijms-20-04076.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (4MB) | Preview

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

Actions (login required)

Edit item Edit item
Provide Feedback