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Open AccessArticle

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

1
Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands
2
Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA
3
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland
4
Department of Medical Biology, Academic Medical Center Amsterdam, Amsterdam 1105AZ, The Netherlands
5
Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
6
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA
7
Departments of Physiology & Cell Biology and Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University College of Medicine Wexner Medical Center, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(17), 4076; https://doi.org/10.3390/ijms20174076
Received: 1 August 2019 / Revised: 16 August 2019 / Accepted: 19 August 2019 / Published: 21 August 2019
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. View Full-Text
Keywords: arrhythmogenic cardiomyopathy; plakophilin-2; second hit; calcium handling; fibrosis; exercise; cardiac pressure overload; inflammation arrhythmogenic cardiomyopathy; plakophilin-2; second hit; calcium handling; fibrosis; exercise; cardiac pressure overload; inflammation
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van Opbergen, C.J.; Noorman, M.; Pfenniger, A.; Copier, J.S.; Vermij, S.H.; Li, Z.; van der Nagel, R.; Zhang, M.; de Bakker, J.M.; Glass, A.M.; Mohler, P.J.; Taffet, S.M.; Vos, M.A.; van Rijen, H.V.; Delmar, M.; van Veen, T.A. Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress. Int. J. Mol. Sci. 2019, 20, 4076.

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