{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:10:00Z","timestamp":1790698200412,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T00:00:00Z","timestamp":1644796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"International Heart and Lung Institute","award":["HL135754, HL135096, HL139348, and HL134824 to P.J.M., HL146969 to M.E.R"],"award-info":[{"award-number":["HL135754, HL135096, HL139348, and HL134824 to P.J.M., HL146969 to M.E.R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1, TV1), CRA_e (Transcript Variant 4, TV4), and an additionally expressed (Transcript Variant 3, TV3) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1+\/\u2212). ZO-1+\/\u2212 mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1+\/\u2212 mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1+\/\u2212 mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1+\/\u2212 cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density (INa) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in ICa current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias.<\/jats:p>","DOI":"10.3390\/cells11040665","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T20:26:42Z","timestamp":1644870402000},"page":"665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Altered Expression of Zonula occludens-1 Affects Cardiac Na+ Channels and Increases Susceptibility to Ventricular Arrhythmias"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3989-0920","authenticated-orcid":false,"given":"Mona","family":"El Refaey","sequence":"first","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Surgery, Division of Cardiac Surgery, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Coles","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Musa","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler L.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel P.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Northwestern Medicine, Chicago, IL 62701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Antwi-Boasiako","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7700-7097","authenticated-orcid":false,"given":"Lindsay J.","family":"Young","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather R.","family":"Manring","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Curran","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Makara","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6333-5041","authenticated-orcid":false,"given":"Kelli","family":"Sas","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Han","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5416-8621","authenticated-orcid":false,"given":"Sara N.","family":"Koenig","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Skaf","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal F.","family":"Kline","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9682-3014","authenticated-orcid":false,"given":"Paul M. L.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Accornero","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maegen A.","family":"Borzok","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Mansfield University of Pennsylvania, Mansfield, PA 17101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Mohler","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"},{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.carpath.2007.01.004","article-title":"Diminished zonula occludens-1 expression in the failing human heart","volume":"16","author":"Laing","year":"2007","journal-title":"Cardiovasc. 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