ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction. Issue 2 (3rd July 2020)

• Record Type: Journal Article
• 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.
• Is Part Of: Circulation research. Volume 127:Issue 2(2020)
• Publication Date: 2020-07-03
• Subjects: atrioventricular block -- connexins -- cytoskeleton -- intercellular junctions -- tight junctions; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.119.316415
• Languages: English
• ISSNs: 0009-7330

Abstract

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. Abstract : Supplemental Digital Content is available in the text.