Abstract 15773: A Novel Role for the Desmosomal Cell-Cell Junction Protein, Desmoplakin, in Mouse Sinoatrial Node Pacemaker Function
Genetic mutations or loss of critical components in desmosomal cell-cell junctions, such as desmoplakin, are associated with arrhythmogenic cardiomyopathies; however, their specific roles have been primarily attributed towards maintaining mechanical integrity of ventricular cardiac muscle cells. A thorough understanding of these structures in cardiac conduction system (CCS) cells is of clinical necessity since increasing evidence points to: 1) their abundant presence in the CCS and 2) findings of conduction system arrhythmias in patients and mouse models harboring cardiomyopathies associated with loss/defects in desmosomal components. To determine a role for desmosomes in the CCS, we generated a novel mouse model through ablation of desmoplakin (DSP csKO) using an inducible Cre/loxP strategy and the hyperpolarizing-activated nucleotide gated channel 4 (Hcn4)-Cre-ERT2 mouse line to mediate postnatal CCS-specific deletion of the desmoplakin gene after tamoxifen administration. Lineage tracing studies revealed the specificity of Hcn4-Cre to target cells of the adult sinoatrial node (SAN), atrioventricular node and the His-Purkinje network. We show that adult DSP csKO are viable; however, conscious telemetry ECGs revealed that these mice have sinus arrhythmias characterized by a strikingly increased number of sinus pauses during rest periods and irregular sinus rhythm, when compared to controls, suggestive of SAN dysfunction. Electron microscopy analyses further revealed that defined desmosomal structures could not be identified in DSP csKO SAN, when compared to controls. Using isolated atrial preparations, we show that control atria had spontaneous and regular depolarizations while DSP csKO atria displayed spontaneous depolarizations of varying rate. We further show using optical mapping, that unlike control atria, which have a well localized leading pacemaker site, DSP csKO display migrating lead pacemaker sites. These results suggest that competition between lead pacemakers might be a mechanistic cause to the sinus pauses observed in DSP csKO mice in vivo. We provide evidence for a novel role of desmoplakin in pacemaker function, which warrants future investigations for desmosomal genes as candidates for human arrhythmias.
- Sinoatrial node
- Heart conduction system
- Genetic techniques
- Molecular biology
- Muscle, cardiac - see Myocardium
- © 2012 by American Heart Association, Inc.