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

International Journal of Molecular Sciences

Stefano Carugo¹  Francesco Lodola²  Milena Bellin³  Francesco Moccia⁴  Elena Sommariva⁵  Ilaria Stadiotti⁵  ChiaraAssunta Pilato⁵  AngelaSerena Maione⁵  Giulio Pompilio⁵ 

[1] Cardiology Unit, San Paolo Hospital, Department of Health Sciences, University of Milan, 20126 Milan, Italy;Center for Nano Science and Technology, Italian Institute of Technology, 20133 Milan, Italy;Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands;Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy;Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy;

关键词: arrhythmogenic cardiomyopathy;    desmosomes;    plakophilin-2;    type 2 ryanodine receptors;    phospholamban;    Ca²⁺ sparks;   

DOI  :  10.3390/ijms20163986

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown