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- Title
Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.
- Authors
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.
- Abstract
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.
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 17, p4076
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20174076