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

Autor: Mingliang Zhang, Chantal J. M. van Opbergen, Maartje Noorman, Harold V.M. van Rijen, Mario Delmar, Sarah H. Vermij, Anna Pfenniger, Jacques M.T. de Bakker, Marc A. Vos, Zhen Li, Roel van der Nagel, Aaron Glass, Jaël S Copier, Steven M. Taffet, Toon A.B. van Veen, Peter J. Mohler
Přispěvatelé: Academic Medical Center
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cardiomyopathy
Haploinsufficiency
030204 cardiovascular system & hematology
Polymerase Chain Reaction
Nervous System Autoimmune Disease
Experimental
lcsh:Chemistry
Electrocardiography
Mice
0302 clinical medicine
Fibrosis
610 Medicine & health
lcsh:QH301-705.5
Spectroscopy
Mice
Knockout
exercise
General Medicine
arrhythmogenic cardiomyopathy
Penetrance
Immunohistochemistry
Pathophysiology
Computer Science Applications
Echocardiography
medicine.symptom
Cardiomyopathies
medicine.medical_specialty
Programmed cell death
Blotting
Western
Inflammation
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Internal medicine
medicine
Journal Article
second hit
Animals
Physical and Theoretical Chemistry
Molecular Biology
Pressure overload
plakophilin-2
business.industry
Organic Chemistry
fibrosis
cardiac pressure overload
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
lcsh:Biology (General)
lcsh:QD1-999
inflammation
calcium handling
570 Life sciences
biology
Calcium
business
Plakophilins
Zdroj: International journal of molecular sciences, 20(17). Multidisciplinary Digital Publishing Institute (MDPI)
International Journal of Molecular Sciences, Vol 20, Iss 17, p 4076 (2019)
International Journal of Molecular Sciences
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) Molecular Diversity Preservation International MDPI 10.3390/ijms20174076
Volume 20
Issue 17
ISSN: 1661-6596
1422-0067
Popis: 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.
Databáze: OpenAIRE
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