| First Author | Dai W | Year | 2020 |
| Journal | Circ Res | Volume | 127 |
| Issue | 2 | Pages | e28-e43 |
| PubMed ID | 32347164 | Mgi Jnum | J:302696 |
| Mgi Id | MGI:6509357 | Doi | 10.1161/CIRCRESAHA.119.316415 |
| Citation | Dai W, et al. (2020) ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction. Circ Res 127(2):e28-e43 |
| abstractText | 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. |
