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 (Tjp1fl/fl; Myh6Cre/Esr1*) were generated by crossing the Tjp1 floxed mice and Myh6Cre/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 (Tjp1fl/fl; Hcn4CreERt2) developed AV block while tamoxifen-induced conduction system deletion of Tjp1 distal to the AV node (Tjp1fl/fl; Kcne1CreERt2) 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.
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 (Tjp1fl/fl; Myh6Cre/Esr1*) were generated by crossing the Tjp1 floxed mice and Myh6Cre/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 (Tjp1fl/fl; Hcn4CreERt2) developed AV block while tamoxifen-induced conduction system deletion of Tjp1 distal to the AV node (Tjp1fl/fl; Kcne1CreERt2) 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.
Authors: Marzia De Bortoli; Alex V Postma; Giulia Poloni; Martina Calore; Giovanni Minervini; Elisa Mazzotti; Ilaria Rigato; Micaela Ebert; Alessandra Lorenzon; Giovanni Vazza; Alberto Cipriani; Riccardo Bariani; Martina Perazzolo Marra; Daniela Husser; Gaetano Thiene; Luciano Daliento; Domenico Corrado; Cristina Basso; Silvio C E Tosatto; Barbara Bauce; J Peter van Tintelen; Alessandra Rampazzo Journal: Circ Genom Precis Med Date: 2018-10
Authors: Matthew A Odenwald; Wangsun Choi; Wei-Ting Kuo; Gurminder Singh; Anne Sailer; Yitang Wang; Le Shen; Alan S Fanning; Jerrold R Turner Journal: J Biol Chem Date: 2018-09-21 Impact factor: 5.157
Authors: Olga Tornavaca; Minghao Chia; Neil Dufton; Lourdes Osuna Almagro; Daniel E Conway; Anna M Randi; Martin A Schwartz; Karl Matter; Maria S Balda Journal: J Cell Biol Date: 2015-03-09 Impact factor: 10.539
Authors: Mona El Refaey; Sara Coles; Hassan Musa; Tyler L Stevens; Michael J Wallace; Nathaniel P Murphy; Steve Antwi-Boasiako; Lindsay J Young; Heather R Manring; Jerry Curran; Michael A Makara; Kelli Sas; Mei Han; Sara N Koenig; Michel Skaf; Crystal F Kline; Paul M L Janssen; Federica Accornero; Maegen A Borzok; Peter J Mohler Journal: Cells Date: 2022-02-14 Impact factor: 6.600
Authors: Junwei Li; Yang Liu; Jiaxing Niu; Changwei Jing; Ning Jiao; Libo Huang; Shuzhen Jiang; Lei Yan; Weiren Yang; Yang Li Journal: Front Microbiol Date: 2022-09-20 Impact factor: 6.064