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Downregulation of <jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub>, as occurs in Brugada syndrome (BrS), causes ventricular arrhythmias. The present study investigated whether the Wnt\/\u03b2\u2010catenin signaling regulates Na<jats:sub>v<\/jats:sub>1.5 in human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes (iPSC\u2010CMs). In healthy male and female iPSC\u2010CMs, activation of Wnt\/\u03b2\u2010catenin signaling by CHIR\u201099021 reduced (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) both Na<jats:sub>v<\/jats:sub>1.5 protein and <jats:italic>SCN5A<\/jats:italic> mRNA. In iPSC\u2010CMs from a BrS patient, both Na<jats:sub>v<\/jats:sub>1.5 protein and peak <jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub> were reduced compared to those in healthy iPSC\u2010CMs. Treatment of BrS iPSC\u2010CMs with Wnt\u2010C59, a small\u2010molecule Wnt inhibitor, led to a 2.1\u2010fold increase in Na<jats:sub>v<\/jats:sub>1.5 protein (<jats:italic>p<\/jats:italic>\u2009=\u20090.0005) but surprisingly did not affect <jats:italic>SCN5A<\/jats:italic> mRNA (<jats:italic>p<\/jats:italic>\u2009=\u20090.146). Similarly, inhibition of Wnt signaling using shRNA\u2010mediated \u03b2\u2010catenin knockdown in BrS iPSC\u2010CMs led to a 4.0\u2010fold increase in Na<jats:sub>v<\/jats:sub>1.5, which was associated with a 4.9\u2010fold increase in peak <jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub> but only a 2.1\u2010fold increase in <jats:italic>SCN5A<\/jats:italic> mRNA. The upregulation of Na<jats:sub>v<\/jats:sub>1.5 by \u03b2\u2010catenin knockdown was verified in iPSC\u2010CMs from a second BrS patient. This study demonstrated that Wnt\/\u03b2\u2010catenin signaling inhibits Na<jats:sub>v<\/jats:sub>1.5 expression in both male and female human iPSC\u2010CMs, and inhibition of Wnt\/\u03b2\u2010catenin signaling upregulates Na<jats:sub>v<\/jats:sub>1.5 in BrS iPSC\u2010CMs through both transcriptional and posttranscriptional mechanisms.<\/jats:p>","DOI":"10.14814\/phy2.15696","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T04:53:20Z","timestamp":1684990400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition of Wnt\/\u03b2\u2010catenin signaling upregulates Na<sub>v<\/sub>1.5 channels in Brugada syndrome <scp>iPSC<\/scp>\u2010derived cardiomyocytes"],"prefix":"10.14814","volume":"11","author":[{"given":"Aizhu","family":"Lu","sequence":"first","affiliation":[{"name":"University of Ottawa Heart Institute  Ottawa Ontario Canada"},{"name":"Department of Cellular and 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