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.
Calcium as a key player in arrhythmogenic cardiomiopathy : adhesion disorder or intracellular alteration? / F. Moccia, F. Lodola, I. Stadiotti, C. Pilato, M. Bellin, S. Carugo, G. Pompilio, E. Sommariva, A.S. Maione. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 20:16(2019 Aug), pp. 3986.1-3986.19.
|Titolo:||Calcium as a key player in arrhythmogenic cardiomiopathy : adhesion disorder or intracellular alteration?|
|Parole Chiave:||Ca2+ sparks; arrhythmogenic cardiomyopathy; desmosomes; phospholamban; plakophilin-2; type 2 ryanodine receptors|
|Settore Scientifico Disciplinare:||Settore MED/11 - Malattie dell'Apparato Cardiovascolare|
|Data di pubblicazione:||ago-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/ijms20163986|
|Appare nelle tipologie:||01 - Articolo su periodico|