ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction

• Published in: Circulation research Vol. 127; no. 2; pp. e28 - e43
• Main Authors: Dai, Wenli, Nadadur, Rangarajan D, Brennan, Jaclyn A, Smith, Heather L, Shen, Kaitlyn M, Gadek, Margaret, Laforest, Brigitte, Wang, Mingyi, Gemel, Joanna, Li, Ye, Zhang, Jing, Ziman, Bruce D, Yan, Jiajie, Ai, Xun, Beyer, Eric C, Lakata, Edward G, Kasthuri, Narayanan, Efimov, Igor R, Broman, Michael T, Moskowitz, Ivan P, Shen, Le, Weber, Christopher R
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 03.07.2020
• Subjects: Animals; Atrioventricular Node - metabolism; Atrioventricular Node - physiology; Connexin 43 - genetics; Connexin 43 - metabolism; Connexins - genetics; Connexins - metabolism; Gap Junction alpha-5 Protein; Heart Rate; Humans; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Potassium Channels, Voltage-Gated - metabolism; Zonula Occludens-1 Protein - genetics; Zonula Occludens-1 Protein - metabolism; tight junctions; connexins; intercellular junctions; cytoskeleton; atrioventricular block
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.119.316415

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.