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

Chantal J.M Van Opbergen,Mario Delmar,Jacques M.T De Bakker,Peter J Mohler,Harold V.M Van Rijen,Sarah H Vermij,Roel Van Der Nagel,Toon A.B Van Veen,Maartje Noorman,Marc A Vos,Mingliang Zhang,Aaron M Glass,Anna Pfenniger,Jaël S Copier,Steven M Taffet,Zhen Li

doi:10.3390/ijms20174076

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.

Highlights

Arrhythmogenic right ventricular cardiomyopathy (ACM) is an inherited heart disease characterized by fibrous or fibrofatty infiltration of the cardiac muscle, ventricular arrhythmias, and increased propensity for sudden death
PKP2 was first described as a component of the desmosome, a cellular structure involved in cell–cell adhesion [7]
The study of Cerrone et al showed that levels of intercalated disk proteins N-cadherin (Ncad), connexin 43 (Cx43), plakoglobin (PKG), and Nav1.5 are normal in PKP2-Hz hearts, the sodium current density and kinetics are affected [15]

Summary

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ACM) is an inherited heart disease characterized by fibrous or fibrofatty infiltration of the cardiac muscle, ventricular arrhythmias, and increased propensity for sudden death. Sudden cardiac arrest most often occurs in early adulthood during the subclinical (or “concealed”) phase of the disease, when overt cardiomyopathy is not yet detectable by imaging, and is the first disease manifestation in a high proportion of probands [1,2,3]. ACM associates primarily with variations in genes coding for desmosomal proteins. One of the most commonly mutated genes in ACM is PKP2, which encodes the desmosomal protein plakophilin-2 (PKP2) [4,5]. Penetrance of the disease is low and it remains unknown which genetic and environmental modifiers are required for development of the cardiomyopathy. Understanding cardiac remodeling upon environmental stress factors is paramount to understand the mechanisms underlying sudden death and deterioration of cardiac performance

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Results

Conclusion