Pitx2c inhibition increases atrial fibroblast activity: Implications in atrial arrhythmogenesis

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Abstract
Background: A Pitx2c deficiency increases the risk of atrial fibrillation (AF). Atrial structural remodelling with fibrosis blocks electrical conduction and leads to arrhythmogenesis. A Pitx2c deficiency enhances profibrotic transforming growth factor (TGF)‐β expression and calcium dysregulation, suggesting that Pitx2c may play a role in atrial fibrosis. The purposes of this study were to evaluate whether a Pitx2c deficiency modulates cardiac fibroblast activity and study the underlying mechanisms.Materials and Methods: A migration assay, proliferation analysis, Western blot analysis and calcium fluorescence imaging were conducted in Pitx2c‐knockdown human atrial fibroblasts (HAFs) using short hairpin (sh)RNA or small interfering (si)RNA.Results: Compared to control HAFs, Pitx2c‐knockdown HAFs had a greater migration but a similar proliferative ability. Pitx2c‐knockdown HAFs had a higher calcium influx with enhanced phosphorylation of calmodulin kinase II (CaMKII), α‐smooth muscle actin and matrix metalloproteinase‐2. In the presence of a CaMKII inhibitor (KN‐93, 0.5 μmol/L), control and Pitx2c‐knockdown HAFs exhibited similar migratory abilities.Conclusion: These findings suggest that downregulation of Pitx2c may regulate atrial fibrosis through modulating calcium homeostasis, which may contribute to its role in anti‐atrial fibrosis, and Pitx2c downregulation may change the atrial electrophysiology and AF occurrence through modulating fibroblast activity.
Funding Information
  • Ministry of Science and Technology, Taiwan (MOST 104‐2314‐B‐038‐032, MOST 105‐2314‐B‐038‐019‐MY2)
  • Taipei Medical University (107‐wf‐eva‐20)

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