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

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_v1.5. As Na_v1.5 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_v1.5 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.