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Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?

1
Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
2
Center for Nano Science and Technology, Italian Institute of Technology, 20133 Milan, Italy
3
Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
4
Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
5
Cardiology Unit, San Paolo Hospital, Department of Health Sciences, University of Milan, 20126 Milan, Italy
6
Department of Clinical Sciences and Community Health, University of Milan, 20126 Milan, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(16), 3986; https://doi.org/10.3390/ijms20163986 (registering DOI)
Received: 26 July 2019 / Revised: 8 August 2019 / Accepted: 14 August 2019 / Published: 16 August 2019
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease. View Full-Text
Keywords: arrhythmogenic cardiomyopathy; desmosomes; plakophilin-2; type 2 ryanodine receptors; phospholamban; Ca2+ sparks arrhythmogenic cardiomyopathy; desmosomes; plakophilin-2; type 2 ryanodine receptors; phospholamban; Ca2+ sparks
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Moccia, F.; Lodola, F.; Stadiotti, I.; Pilato, C.A.; Bellin, M.; Carugo, S.; Pompilio, G.; Sommariva, E.; Maione, A.S. Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration? Int. J. Mol. Sci. 2019, 20, 3986.

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