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

ABSTRACT:

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^fl/fl; Myh6^Cre/Esr1*) were generated by crossing the Tjp1 floxed mice and Myh6^Cre/Esr1* 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^fl/fl; Hcn4^CreERt2) developed AV block while tamoxifen-induced conduction system deletion of Tjp1 distal to the AV node (Tjp1^fl/fl; Kcne1^CreERt2) 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.

SUBMITTER: Dai W 

PROVIDER: S-EPMC7334106 | biostudies-literature |

REPOSITORIES: biostudies-literature