Pitx2c inhibition increases atrial fibroblast activity: Implications in atrial arrhythmogenesis

Yu Hsun Kao, Cheng Chih Chung, Wan Li Cheng, Baigalmaa Lkhagva, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Article numbere13160
JournalEuropean Journal of Clinical Investigation
Issue number10
Publication statusPublished - Oct 1 2019


  • atrial fibrillation
  • cardiac fibroblast
  • cell migration
  • intracellular calcium
  • Pitx2c

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry


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