Abstract 14680: Loss of Intercalated Disc Protein mXinβ Leads to Atrioventricular Conduction Defects and Channel Remodeling
Intercalated discs (ICDs) transmit mechanical force and electrical impulses, organize assembly of certain ion channels and transduce signals. The mouse orthologs (mXinα and mXinβ) of human cardiomyopathy-associated genes (CMYA1 and CMYA3, respectively) encode proteins localized to ICDs. Ablation of mXinα leads to late-onset cardiomyopathy with conduction defects. Our recent reports that mXinα interacts with KChIP2 and cortactin, which influence surface expression of Ito and IK, slow1, provide a novel mechanism for the reduced Ito and IK in mXinα-null cardiomyocytes. On the other hand, mXinβ is required for the postnatal maturation of ICDs and the localization of mXinα to ICDs. Therefore, we hypothesized that mXinβ also plays a role in cardiac electrophysiology. Supporting this hypothesis, surface ECG recording showed significantly prolonged PR, QT and QTc in 14-17 day-old mXinβ-null mice. Furthermore, 18-day-old mXinβ-null mice had 100% incidence of second or third degree AV block, while wildtype controls had 0. Supporting AV conduction defects, mXinβ-null hearts had hypoplastic atrioventricular node, malformed His-bundle and bundle branches that reduced connexin 40 expression. Optical mapping revealed a 45% reduction of conduction velocity in left ventricles of mutants. Potentially compensating for reduced intercellular coupling, mXinβ-null cardiomyocytes had significantly higher action potential amplitudes, more positive maximum diastolic potentials and faster repolarization. Consistently, mutant cardiomyocytes significantly reduced Ito, but increased IK and IK1 current densities. The electrophysiological remodeling in mutant cells correlates with their down-regulation of Kv4.2 and Kv4.3 and up-regulation of Kv1.5 and Nav1.5. We conclude that mXinβ is required for the development and function of ventricular conduction system and it regulates the expression and function of ICD-localized channels Kv4.2, Kv4.3, Kv1.5 and Nav1.5. The morphological defects, AV conduction defects, and ionic current remodeling of mXinβ-null hearts phenocopy that of Nkx2.5-deficient hearts. Given that Xin is downstream of Nkx2.5, we propose that mXinβ is a mediator of Nkx2.5’s roles in cardiac electrophysiology.
- © 2013 by American Heart Association, Inc.