Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis

Abstract

IntroductionCyclase-associated protein 2 (CAP2) plays a major role in regulating the actin cytoskeleton. Since inactivation of CAP2 in a mouse model by a gene trap approach (Cap2gt/gt) results in cardiomyopathy and increased mortality, we hypothesized that CAP2 has a major impact on arrhythmias and electrophysiological parameters.Material and methodsWe performed long-term-ECG recordings in transgenic CAP2 deficient mice (C57BL/6) to detect spontaneous arrhythmias. In vivo electrophysiological studies by right heart catheterization and ex vivo epicardial mapping were used to analyze electrophysiological parameters, the inducibility of arrhythmias, and conduction velocities. Expression and distribution of cardiac connexins and the amount of cardiac fibrosis were evaluated.ResultsSpontaneous ventricular arrhythmias could be detected in Cap2gt/gt during the long-term-ECG recording. Cap2gt/gt showed marked conduction delays at atrial and ventricular levels, including a reduced heart rate (421.0 ±40.6 bpm vs. 450.8 ±27.9 bpm; p < 0.01), and prolongations of PQ (46.3 ±4.1 ms vs. 38.6 ±6.5 ms; p < 0.01), QRS (16.2 ±2.6 ms vs. 12.6 ±1.4 ms; p < 0.01), and QTc interval (55.8 ±6.0 ms vs. 45.2 ±3.3 ms; p = 0.02) in comparison to wild type mice. The PQ prolongation was due to an infra-Hisian conduction delay (HV: 9.7 ±2.1 ms vs. 6.5 ±3.1 ms; p = 0.02). The inducibility of ventricular tachycardias during the electrophysiological studies was significantly elevated in the mutant mice (inducible animals: 88% vs. 33%; p = 0.04). Cap2gt/gt showed more abnormal distribution of connexin43 compared to WT (23.0 ±4.7% vs. 2.9 ±0.8%; p < 0.01). Myocardial fibrosis was elevated in Cap2gt/gt hearts (9.1 ±6.7% vs. 5.5 ±3.3%; p < 0.01).ConclusionsLoss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias. Structural changes in Cap2gt/gt are associated with alterations in myocardial connexins and fibrosis.

CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function

“…Notably, human CAP2 has been localized to 6p22.3, and interstitial deletions of variable sizes encompassing the CAP2 locus have been associated with clinical symptoms including developmental delay, hypotonia, and heart defects (36–38). While we showed here developmental delay and hypotonia for CAP2 mutant mice, others previously reported heart defects (13, 14, 39). We therefore propose that loss of CAP2 causes or contributes to the pathology of 6p22.3 deletion syndrome.…”

CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy

“…Potentially, CAP2 could be the causative gene in this interval based on effects found in heterozygous mice including dilation of the heart27 and increase in inducibility of ventricular tachycardia 27. However, in our study, all heterozygotes: six adults and four children did not present any cardiac abnormality, negating this possibility in humans.…”

CAPt’n of Actin Dynamics: Recent Advances in the Molecular, Developmental and Physiological Functions of Cyclase-Associated Protein (CAP)

“…This led to the suggestion that vertebrate CAPs evolved cell type-specific functions (Ono, 2013), similar to the muscle-specific function of CAS-1 in C. elegans (Nomura et al, 2012). Although abundance in striated muscles has been reported for CAP2 in several species from frog (Xenopus laevis) and zebrafish (Danio rerio) to mammals (Bertling et al, 2004;Peche et al, 2007;Wolanski et al, 2009;Effendi et al, 2012), its function in striated muscles has been studied only in mice, in which systemic inactivation caused a dilated cardiomyopathy (DCM) together with impaired cardiac conduction (Peche et al, 2012;Stockigt et al, 2016). These defects might be caused by disturbed sarcomere organization and/or by reduced cooperativity of calcium-induced force generation, which have been both shown for isolated CAP2 mutant myofibrils (Peche et al, 2012).…”