Plakophilin-2 deficiency in adult murine ventricular myocytes disrupts intracellular calcium homeostasis and causes isoproterenol-induced arrhythmias that are prevented by flecainide.
Does cardiomyocyte-specific loss of PKP2 cause arrhythmogenic cardiomyopathy and disrupt calcium cycling in adult mice?
PKP2 deficiency in adult cardiomyocytes disrupts intracellular calcium homeostasis and causes life-threatening arrhythmias even before overt structural disease, suggesting a novel arrhythmogenic mechanism in ARVC.
Abstract Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell–cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for Ca V 1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.
Cerrone et al. (Mon,) conducted a other in Arrhythmogenic right ventricular cardiomyopathy (ARVC). PKP2 knockout vs. Cre-negative littermates was evaluated on Isoproterenol-induced arrhythmias and intracellular calcium homeostasis. Plakophilin-2 deficiency in adult murine ventricular myocytes disrupts intracellular calcium homeostasis and causes isoproterenol-induced arrhythmias that are prevented by flecainide.