Abstract 1475: Cardiac-specific Disruption Of Coxsackievirus And Adenovirus Receptor (car) Leads To Cardiomyopathy With Disorganization Of Intercalated Discs And Complete Atrioventricular Block
The coxsackievirus and adenovirus receptor’s (CAR) role as a viral receptor is known; however, its precise function in the heart is not clear. The structure of CAR is similar to adhesion molecules. In the adult heart, the majority of CAR localizes at the intercalated disc. Germ line CAR deletion induces embryonic lethality at E11.5 with evidence of a cardiac abnormality. To understand the physiological role of CAR in the cardiac myocyte, we generated cardiac-specific CAR knockout mice using a CAR floxed allele and α-MHC-CRE mice. There was no evidence of cardiac dysfunction until 4 months of age. Immunoblot analysis of ventricles at 4 weeks post natal, prior to detectable evidence of cardiomyopathy, demonstrated a significant decrease in β-catenin and ZO-1 levels to approximately 30% of wild type levels in cardiac-specific CAR knockout mice; (n=3 in each group). There was no significant difference in total pan-cadherin, α-catenin, vinculin, connexin43, or caveolin3 levels. Immunostain at 4 weeks showed a decrease in localization of β-catenin and ZO-1 at the intercalated disc. Echocardiography at 6 months showed severe cardiac dysfunction (LVEDD= 4.23±0.09 Vs 3.98±0.27, LVESD= 3.31±0.13 vs 1.89±0.24, FS= 21.94±2.11 vs 46.28±1.77, CAR knockout vs WT, respectively). At six months, H&E and Trichrome staining revealed fibrosis with minimal inflammation. Electrocardiograms demonstrated complete atrioventricular dissociation from 4 weeks, consistent with complete AV block. Using mice that express GFP in the conduction system (HCN4-GFP knock-in mice) we demonstrated expression of CAR in the normal AV node.
Conclusion: CAR expression is required for normal ventricular function, AV conduction and organization of the intercalated disc in the adult ventricular myocyte. This indicates that CAR has an important role the normal function of conduction system and as an intercalated disc adhesion molecule involved in normal β-catenin and ZO-1 localization.