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.

Moccia, F., Lodola, F., Stadiotti, I., Pilato, C., Bellin, M., Carugo, S., et al. (2019). Calcium as a key player in arrhythmogenic cardiomyopathy: Adhesion disorder or intracellular alteration?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 20(16) [10.3390/ijms20163986].

Calcium as a key player in arrhythmogenic cardiomyopathy: Adhesion disorder or intracellular alteration?

Lodola F
Co-primo
;
2019

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.
Articolo in rivista - Review Essay
Arrhythmogenic cardiomyopathy; Ca; 2+; sparks; Desmosomes; Phospholamban; Plakophilin-2; Type 2 ryanodine receptors;
Arrhythmogenic cardiomyopathy, calcium handling
English
Moccia, F., Lodola, F., Stadiotti, I., Pilato, C., Bellin, M., Carugo, S., et al. (2019). Calcium as a key player in arrhythmogenic cardiomyopathy: Adhesion disorder or intracellular alteration?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 20(16) [10.3390/ijms20163986].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/276131
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