ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction

Circ Res. 2020 Jul 3;127(2):e28-e43. doi: 10.1161/CIRCRESAHA.119.316415. Epub 2020 Apr 29.


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.

Keywords: atrioventricular block; connexins; cytoskeleton; intercellular junctions; tight junctions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*


  • Connexin 43
  • Connexins
  • Kcne1 protein, mouse
  • Myh6 protein, mouse
  • Potassium Channels, Voltage-Gated
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • Myosin Heavy Chains