ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.

RATIONALE:ZO-1 (Zona occludens 1), encoded by the tight junction protein 1 (TJP1) gene, is a regulator of paracellular permeability in epithelia and endothelia. ZO-1 interacts with the actin cytoskeleton, gap, and adherens junction proteins and localizes to intercalated discs in cardiomyocytes. However, the contribution of ZO-1 to cardiac physiology remains poorly defined. OBJECTIVE:We aim to determine the role of ZO-1 in cardiac function. METHODS AND RESULTS:Inducible cardiomyocyte-specific Tjp1 deletion mice (Tjp1; Myh6) were generated by crossing the Tjp1 floxed mice and Myh6 transgenic mice. Tamoxifen-induced loss of ZO-1 led to atrioventricular (AV) block without changes in heart rate, as measured by ECG and ex vivo optical mapping. Mice with tamoxifen-induced conduction system-specific deletion of Tjp1 (Tjp1; Hcn4) developed AV block while tamoxifen-induced conduction system deletion of Tjp1 distal to the AV node (Tjp1; Kcne1) did not demonstrate conduction defects. Western blot and immunostaining analyses of AV nodes showed that ZO-1 loss decreased Cx (connexin) 40 expression and intercalated disc localization. Consistent with the mouse model study, immunohistochemical staining showed that ZO-1 is abundantly expressed in the human AV node and colocalizes with Cx40. Ventricular conduction was not altered despite decreased localization of ZO-1 and Cx43 at the ventricular intercalated disc and modestly decreased left ventricular ejection fraction, suggesting ZO-1 is differentially required for AV node and ventricular conduction. CONCLUSIONS:ZO-1 is a key protein responsible for maintaining appropriate AV node conduction through maintaining gap junction protein localization.

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