Key result
LQT3-causing SCN5A mutation drives cardiac fibrosis via abnormal calcium signaling and increased fibroblast proliferation.
Why the study?
Because Nav1.5 is expressed in cardiac fibroblasts as well as cardiomyocytes, the authors investigated whether the LQT3-causing p.ΔQKP1507-1509 SCN5A mutation alters cardiac fibroblast phenotype.
Does the LQT3-causing p.ΔQKP1507-1509 SCN5A mutation alter cardiac fibroblast phenotype in a mouse model?
Does the LQT3-causing p.ΔQKP1507-1509 SCN5A mutation alter cardiac fibroblast phenotype in a mouse model?
Cardiac fibroblasts carrying the LQT3-causing ΔQKP-SCN5A mutation exhibit an abnormal, proliferative and pro-fibrotic phenotype driven by abnormal calcium signaling.
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 Na v 1.5. As Na v 1.5 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 Na v 1.5 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.
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Castro et al. (2025) studied Long QT syndrome type 3 (LQT3). Scn5a+/ΔQKP mutation vs. Control fibroblasts/tissue was evaluated on Fibroblast proliferation, survival, TGF-β expression, and fibrosis. The LQT3-causing p.ΔQKP1507-1509 SCN5A mutation increases cardiac fibroblast proliferation, survival, and TGF-β expression, leading to augmented fibrosis via abnormal calcium signaling.
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