Journal
EXPERIMENTAL CELL RESEARCH
Volume 321, Issue 2, Pages 178-189Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2013.12.014
Keywords
Catecholaminergic polymorphic ventricular tachycardia; CASQ2 mutation; CASQ2 knock-out; ER stress
Categories
Funding
- Italian Telethon ONLUS Foundation [GGP11141]
- CARIPLO Foundation
- PRIN [2010BWY8E9_003]
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Cardiac calsequestrin (CASQ2) contributes to intracellular Ca2+ homeostasis by virtue of its low-affinity/high-capacity Ca2+ binding properties, maintains sarcoplasmic reticulum (SR) architecture and regulates excitation-contraction coupling, especially or exclusively upon beta-adrenergic stimulation. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children or young adults. Recessive CPVT variants are due to mutations in the CASQ2 gene. Molecular and ultra-structural properties were studied in hearts of CASQ2(R33Q/R33Q) and of CASQ2(-/-) mice from post-natal day 2 to week 8. The drastic reduction of CASQ2-R33Q is an early developmental event and is accompanied by down-regulation of triadin and junctin, and morphological changes of jSR and of SR-transverse-tubule junctions. Although endoplasmic reticulum stress is activated, no signs of either apoptosis or autophagy are detected. The other model of recessive CPVT, the CA5Q2(-/-) mouse, does not display the same adaptive pattern. Expression of CASQ2-R33Q influences molecular and ultra-structural heart development; post-natal, adaptive changes appear capable of ensuring until adulthood a new pathophysiological equilibrium. (C) 2014 Elsevier Inc. All rights reserved.
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