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As Na<jats:sub>v<\/jats:sub>1.5 is expressed in cardiomyocytes but also in cardiac fibroblasts, we investigated whether the LQT3-causing p.\u0394QKP1507-1509 (\u0394QKP) <jats:italic>SCN5A<\/jats:italic> mutation alters cardiac fibroblast phenotype. Primary cultured ventricular fibroblasts from <jats:italic>Scn5a<\/jats:italic>\n            <jats:sup>+\/\u0394QKP<\/jats:sup> knock-in mice showed increased proliferation, survival, expression of transforming growth factor-\u03b2 (TGF-\u03b2) and activation of its canonical pathway, and reduced \u03b1-smooth muscle actin expression. Ventricular tissue from <jats:italic>Scn5a<\/jats:italic>\n            <jats:sup>+\/\u0394QKP<\/jats:sup> mice exhibited augmented fibroblast populations and fibrosis. Inhibiting TGF-\u03b2 receptor, sodium current or <jats:italic>Scn5a<\/jats:italic> expression decreased <jats:italic>Scn5a<\/jats:italic>\n            <jats:sup>+\/\u0394QKP<\/jats:sup> fibroblast proliferation, while veratridine increased proliferation of control fibroblasts, mimicking Na<jats:sub>v<\/jats:sub>1.5 gain-of-function. Lastly, abnormal calcium signaling underlied the increased proliferation of <jats:italic>Scn5a<\/jats:italic>\n            <jats:sup>+\/\u0394QKP<\/jats:sup> fibroblasts. Our study shows that cardiac fibroblasts carrying the \u0394QKP-<jats:italic>SCN5A<\/jats:italic> mutation exhibit an abnormal, proliferative phenotype, paving the way for better understanding the role of cardiac fibroblasts in LQT3.<\/jats:p>","DOI":"10.1038\/s42003-025-07636-5","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T19:18:51Z","timestamp":1739301531000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Long QT syndrome type 3 gain-of-function of Nav1.5 increases ventricular fibroblasts proliferation and pro-fibrotic factors"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6309-1689","authenticated-orcid":false,"given":"Claire","family":"Castro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Patin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1382-6938","authenticated-orcid":false,"given":"Cyrielle","family":"Jajkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Chizelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia Ore","family":"Cerpa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-9841","authenticated-orcid":false,"given":"Agn\u00e8s","family":"Tessier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Le Pogam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imen","family":"Fellah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4850-4171","authenticated-orcid":false,"given":"Isabelle","family":"Bar\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavien","family":"Charpentier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-9901","authenticated-orcid":false,"given":"Micka\u00ebl","family":"Derangeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"7636_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.cpcardiol.2018.04.002","volume":"44","author":"S. 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