kn-93 and Atrial-Remodeling

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.. 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.. 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.. 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.

Topics: Actins; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Remodeling; Benzylamines; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Movement; Cell Proliferation; Down-Regulation; Fibroblasts; Fibrosis; Gene Knockdown Techniques; Heart Atria; Homeobox Protein PITX2; Homeodomain Proteins; Humans; In Vitro Techniques; Matrix Metalloproteinase 2; Optical Imaging; Phosphorylation; Protein Isoforms; Protein Kinase Inhibitors; RNA, Small Interfering; Sulfonamides; Transcription Factors