{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T20:19:00Z","timestamp":1769113140774,"version":"3.49.0"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":3682,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2015,12,21]],"date-time":"2015-12-21T00:00:00Z","timestamp":1450656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Garfield Weston Trust"},{"name":"NIHR Bristol Biomedical Research Unit in Cardiovascular Medicine"},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes. Little is known about ZO-2 expression and function in the human heart. Here, we examinedthe hypothesis that chronic hypoxia down-regulates ZO-2 expression in human myocardium and cultured rat cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Patients with a diagnosis of cyanotic (n = 10) or acyanotic (n = 10) Tetralogy of Fallot undergoing surgical repair were used to examine ZO-2 messenger RNA and protein expression by real time-PCR, immunohistochemistry, and western blotting. A model of cultured rat cardiomyocytes wasused to measure ZO-2 and AJ proteins levels in response to hypoxia and to investigate ZO-2 cellular localization. We showed that ZO-2 is expressed in myocardial tissue in acyanotic and cyanotic children with congenital heart defects. ZO-2 was specifically down-regulated in cyanotic myocardium at both the messenger RNA and protein levels when compared with acyanotic patients. This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis. Furthermore, in addition to its cytoplasmic expression, ZO-2 showed nuclear expression in cultured rat cardiomyocytes suggesting potential role in transcription regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hypoxia down-regulates ZO-2 expression in both cyanotic patient's myocardium and cultured rat cardiomyocytes. This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.12081","type":"journal-article","created":{"date-parts":[[2015,12,21]],"date-time":"2015-12-21T08:51:11Z","timestamp":1450687871000},"page":"131-137","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chronic Hypoxia down-Regulates Tight Junction Protein ZO-2 Expression in Children with Cyanotic Congenital Heart Defect"],"prefix":"10.1093","volume":"3","author":[{"given":"Emma L.","family":"Jenkins","sequence":"first","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Caputo","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianni D.","family":"Angelini","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed T.","family":"Ghorbel","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol , Bristol ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,12,21]]},"reference":[{"key":"2026012115141797400_ehf212081-bib-0001","first-page":"H632","article-title":"Correlation between antioxidant changes during hypoxia and recovery on reoxygenation","volume":"261","author":"Dhaliwal","year":"1991","journal-title":"Am J Physiol"},{"key":"2026012115141797400_ehf212081-bib-0002","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S1010-7940(05)80075-2","article-title":"Reduction of reoxygenation injury and nitric oxide production in the cyanotic immature heart by controlling pO2","volume":"9","author":"Ihnken","year":"1995","journal-title":"Eur J Cardiothorac Surg"},{"key":"2026012115141797400_ehf212081-bib-0003","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0022-5223(19)34848-2","article-title":"Effect of oxygen tension and cardiovascular operations on the myocardial antioxidant enzyme activities in patients with tetralogy of fallot and aorta-coronary bypass","volume":"104","author":"Teoh","year":"1992","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2026012115141797400_ehf212081-bib-0004","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/0002-9149(81)90079-5","article-title":"Intracardiac surgery in infants under age 3 months: incremental risk factors for hospital mortality","volume":"48","author":"Kirklin","year":"1981","journal-title":"Am J Cardiol"},{"key":"2026012115141797400_ehf212081-bib-0005","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jtcvs.2009.12.055","article-title":"Transcriptomic analysis of patients with tetralogy of fallot reveals the effect of chronic hypoxia on myocardial gene expression","volume":"140","author":"Ghorbel","year":"2010","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2026012115141797400_ehf212081-bib-0006","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1073\/pnas.88.8.3460","article-title":"Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1","volume":"88","author":"Gumbiner","year":"1991","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026012115141797400_ehf212081-bib-0007","doi-asserted-by":"crossref","first-page":"35179","DOI":"10.1074\/jbc.274.49.35179","article-title":"Protein interactions at the tight junction. 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