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ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.
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.
Afiliação
  • Dai W; From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.
  • Nadadur RD; Pediatrics, Pathology, and Human Genetics (R.D.N., K.M.S., M.G., I.P.M.), The University of Chicago, IL.
  • Brennan JA; Department of Biomedical Engineering, The George Washington University, Washington, DC (J.A.B., I.R.E.).
  • Smith HL; From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.
  • Shen KM; Pediatrics, Pathology, and Human Genetics (R.D.N., K.M.S., M.G., I.P.M.), The University of Chicago, IL.
  • Gadek M; Pediatrics, Pathology, and Human Genetics (R.D.N., K.M.S., M.G., I.P.M.), The University of Chicago, IL.
  • Laforest B; Medicine, Section of Cardiology (B.L., M.T.B.), The University of Chicago, IL.
  • Wang M; Laboratory of Cardiovascular Science, National Institution on Aging-NIH, Baltimore, MD (M.W., J.Z., B.D.Z., E.G.L.).
  • Gemel J; Pediatrics (J.G., E.C.B.), The University of Chicago, IL.
  • Li Y; From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.
  • Zhang J; Laboratory of Cardiovascular Science, National Institution on Aging-NIH, Baltimore, MD (M.W., J.Z., B.D.Z., E.G.L.).
  • Ziman BD; Laboratory of Cardiovascular Science, National Institution on Aging-NIH, Baltimore, MD (M.W., J.Z., B.D.Z., E.G.L.).
  • Yan J; Physiology and Biophysics, Rush University, Chicago, IL (J.Y., X.A.).
  • Ai X; Physiology and Biophysics, Rush University, Chicago, IL (J.Y., X.A.).
  • Beyer EC; Pediatrics (J.G., E.C.B.), The University of Chicago, IL.
  • Lakata EG; Laboratory of Cardiovascular Science, National Institution on Aging-NIH, Baltimore, MD (M.W., J.Z., B.D.Z., E.G.L.).
  • Kasthuri N; Neurobiology (N.K.), The University of Chicago, IL.
  • Efimov IR; Department of Biomedical Engineering, The George Washington University, Washington, DC (J.A.B., I.R.E.).
  • Broman MT; Medicine, Section of Cardiology (B.L., M.T.B.), The University of Chicago, IL.
  • Moskowitz IP; Pediatrics, Pathology, and Human Genetics (R.D.N., K.M.S., M.G., I.P.M.), The University of Chicago, IL.
  • Shen L; From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.
  • Weber CR; Surgery, Section of Neurosurgery (L.S.), The University of Chicago, IL.
Circ Res ; 127(2): e28-e43, 2020 07 03.
Article em En | MEDLINE | ID: mdl-32347164
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 (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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Nó Atrioventricular / Proteína da Zônula de Oclusão-1 / Frequência Cardíaca Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Nó Atrioventricular / Proteína da Zônula de Oclusão-1 / Frequência Cardíaca Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article