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 journalArticle

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.

Original languageEnglish
Article numbere13160
JournalEuropean Journal of Clinical Investigation
Volume49
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry

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