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

Autor: van Opbergen CJM; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., Noorman M; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., Pfenniger A; Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA., Copier JS; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., Vermij SH; Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA.; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland., Li Z; Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA., van der Nagel R; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., Zhang M; Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA., de Bakker JMT; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands.; Department of Medical Biology, Academic Medical Center Amsterdam, Amsterdam 1105AZ, The Netherlands., Glass AM; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA., Mohler PJ; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA.; 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., Taffet SM; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA., Vos MA; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., van Rijen HVM; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands., Delmar M; Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA., van Veen TAB; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands. a.a.b.vanveen@umcutrecht.nl.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2019 Aug 21; Vol. 20 (17). Date of Electronic Publication: 2019 Aug 21.
DOI: 10.3390/ijms20174076
Abstrakt: 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 Ca 2+ 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 Ca 2+ -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 Ca 2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.
Databáze: MEDLINE
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