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- Title
Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?
- Authors
Moccia, Francesco; Lodola, Francesco; Stadiotti, Ilaria; Pilato, Chiara Assunta; Bellin, Milena; Carugo, Stefano; Pompilio, Giulio; Sommariva, Elena; Maione, Angela Serena
- 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.
- Subjects
ASSOCIATION for Computing Machinery; RYANODINE receptors; CARDIOMYOPATHIES; GENETIC disorders; SARCOPLASMIC reticulum; THERAPEUTICS; HEART diseases; CONTRACTILITY (Biology); CARDIAC contraction
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 16, p3986
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20163986