Basic/Translational Science -> Whole Animal Electrophysiology and Pharmacology (includes Neurohumoral Modulation) D-PO06 - Poster Session VI (ID 26) Poster

D-PO06-014 - Inhibition Of Kca3.1 Suppresses Atrial Fibrillation Through Attenuating Atrial Fibrosis And Inflammation In Canines With Prolonged Atrial Pacing (ID 1341)

 Q. zhao: Nothing relevant to disclose.


Background: Atrial fibrosis plays a key role in the maintenance of atrial fibrillation (AF). Recent studies indicated that KCa3.1 channel has a close relationship with cardiac fibrosis.
Objective: The study was to observe the effect of KCa3.1 channel inhibitor (TRAM-34) on atrial fibrosis and inflammation in canines with atrial pacing and he effect of KCa3.1 on atrial fibroblasts in vitro.
Methods: Twenty-two beagles were randomized into control, pacing and TRAM-34 groups. Canines in the pacing group underwent atrial pacing for 1 week at 450 bpm. The canines in the TRAM-34 group received atrial pacing and TRAM-34 (5mg/kg) intraperitoneal injection twice a day for 1 week. After that, atrial electrophysiology and biochemical factors were investigated. Atrial fibroblasts were cultured in vitro. TRAM-34 was added in the Angiotensin II (Ang II)-induced fibroblasts. Fibroblasts were overexpressed with a recombinant adenovirus vector carrying the KCa3.1 gene to detect the fibrosis.
Results: Expression of KCa3.1 channel in the atrium has closely association with complex fractionated atrial electrograms in pacing group. TRAM-34 significantly prevents the shorten of atrial refractoriness and conduction time, and reduced AF vulnerability in beagles subjected to 7 days atrial tachypacing. Levels of KCa3.1 channel and Ang-II in the atrium significantly increased in the pacing group than that in the control and TRAM-34 groups. TRAM-34 attenuated the atrial interstitial fibrosis and the expression of collagen I and α-SMA and remarkably decreased the levels of MCP-1 and CXCL16. In vitro, KCa3.1 expression was up-regulated in the Ang II-induced fibrosis model. TRAM-34 significantly reduced the increase of collagen I and α-SMA expression induced by Ang II. After overexpression with KCa3.1 in fibroblasts, collagen I, α-SMA, MCP-1 and CXCL16 were significantly up-regulated, and TGF-β1 and Smad3 signaling pathways were activated. TRAM-34 can significantly reduce their expression.
Conclusion: KCa3.1 channel plays an important role in atrial fibrosis andTRAM-34 suppresses AF through attenuating atrial fibrosis and inflammation. The effects of KCa3.1 channel on fibrosis and inflammation is closely associated with TGF-β1 and Smad3 signaling pathways.