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<p>The long QT syndrome type 3 (LQT3) is a cardiac channelopathy caused by gain-of-function mutations in the <i>SCN5A</i> gene, encoding the sodium channel Na<sub>v</sub>1.5. As Na<sub>v</sub>1.5 is expressed in cardiomyocytes but also in cardiac fibroblasts, we investigated whether the LQT3-causing p.ΔQKP1507-1509 (ΔQKP) <i>SCN5A</i> mutation alters cardiac fibroblast phenotype. Primary cultured ventricular fibroblasts from <i>Scn5a</i><sup>+/ΔQKP</sup> knock-in mice showed increased proliferation, survival, expression of transforming growth factor-β (TGF-β) and activation of its canonical pathway, and reduced α-smooth muscle actin expression. Ventricular tissue from <i>Scn5a</i><sup>+/ΔQKP</sup> mice exhibited augmented fibroblast populations and fibrosis. Inhibiting TGF-β receptor, sodium current or <i>Scn5a</i> expression decreased <i>Scn5a</i><sup>+/ΔQKP</sup> fibroblast proliferation, while veratridine increased proliferation of control fibroblasts, mimicking Na<sub>v</sub>1.5 gain-of-function. Lastly, abnormal calcium signaling underlied the increased proliferation of <i>Scn5a</i><sup>+/ΔQKP</sup> fibroblasts. Our study shows that cardiac fibroblasts carrying the ΔQKP-<i>SCN5A</i> mutation exhibit an abnormal, proliferative phenotype, paving the way for better understanding the role of cardiac fibroblasts in LQT3.</p>

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Long QT syndrome type 3 gain-of-function of Nav1.5 increases ventricular fibroblasts proliferation and pro-fibrotic factors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月11日

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  • Claire Castro,
  • Justine Patin,
  • Cyrielle Jajkiewicz,
  • Franck Chizelle,
  • Cynthia Ore Cerpa,
  • Agnès Tessier,
  • Eva Le Pogam,
  • Imen Fellah,
  • Isabelle Baró,
  • Flavien Charpentier,
  • Mickaël Derangeon

摘要

The long QT syndrome type 3 (LQT3) is a cardiac channelopathy caused by gain-of-function mutations in the SCN5A gene, encoding the sodium channel Nav1.5. As Nav1.5 is expressed in cardiomyocytes but also in cardiac fibroblasts, we investigated whether the LQT3-causing p.ΔQKP1507-1509 (ΔQKP) SCN5A mutation alters cardiac fibroblast phenotype. Primary cultured ventricular fibroblasts from Scn5a+/ΔQKP knock-in mice showed increased proliferation, survival, expression of transforming growth factor-β (TGF-β) and activation of its canonical pathway, and reduced α-smooth muscle actin expression. Ventricular tissue from Scn5a+/ΔQKP mice exhibited augmented fibroblast populations and fibrosis. Inhibiting TGF-β receptor, sodium current or Scn5a expression decreased Scn5a+/ΔQKP fibroblast proliferation, while veratridine increased proliferation of control fibroblasts, mimicking Nav1.5 gain-of-function. Lastly, abnormal calcium signaling underlied the increased proliferation of Scn5a+/ΔQKP fibroblasts. Our study shows that cardiac fibroblasts carrying the ΔQKP-SCN5A mutation exhibit an abnormal, proliferative phenotype, paving the way for better understanding the role of cardiac fibroblasts in LQT3.