α-adrenoceptor-mediated enhanced inducibility of atrial fibrillation in a canine system inflammation model

Chen,Ying‑Ying; Sun,Ze‑Wei; Jiang,Jian‑Ping; Kang,Xiao‑Dong; Wang,Lin‑Lin; Shen,Yue‑Liang; Xie,Xu‑Dong; Zheng,Liang‑Rong

doi:10.3892/mmr.2017.6477

α-adrenoceptor-mediated enhanced inducibility of atrial fibrillation in a canine system inflammation model

Authors:
- Ying‑Ying Chen
- Ze‑Wei Sun
- Jian‑Ping Jiang
- Xiao‑Dong Kang
- Lin‑Lin Wang
- Yue‑Liang Shen
- Xu‑Dong Xie
- Liang‑Rong Zheng
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Affiliations: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China, Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China, Department of Clinical Medicine, Zhejiang Medical College, Hangzhou, Zhejiang 310053, P.R. China, Experimental Animal Center, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China, Center for Stem Cell and Tissue Engineering, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
Published online on: April 13, 2017 https://doi.org/10.3892/mmr.2017.6477
Pages: 3767-3774

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Abstract

The exact mechanism associated with inflammation and atrial fibrillation (AF) remains unknown. The aim of the present study was to investigate the roles of connexin 43 (Cx43) and a1‑adrenergic receptor (α1‑AR) activation in the pathogenesis of system inflammation‑induced AF. A canine model of chronic low‑grade system inflammation was established by administrating a low dose of lipopolysaccharide (LPS; 0.1 µg/kg) for 2 weeks. Programmed stimulation was applied on the right atrial appendage to determine the effective refractory periods (ERP) and the window of vulnerability (WOV). Tumor necrosis factor α (TNF‑α) and interleukin 6 (IL‑6) levels in plasma and atrial tissue were measured by ELISA. Cx43, Toll‑like receptor 4 (TLR4) and nuclear factor κB (NF‑κB) proteins were analyzed using western blotting or immunohistochemistry. Administration of LPS for 2 weeks increased the concentration of TNF‑α and IL‑6 in the plasma and right atrium. ERP was markedly shortened and cumulative WOV was significantly widened in the LPS group. Following treatment with LPS, the amount of Cx43 protein in the area of intercalated disk increased. In addition, a high‑density of Cx43 in the lateral connection was identified. LPS also induced the activation of NF‑κB in the canine atrium. Administration with the α1‑AR blocker doxazosin prevented the production of LPS‑induced inflammatory cytokine and reversed the enhanced vulnerability to atrial fibrillation. Doxazosin inhibited the LPS‑induced increase in Cx43 protein and heterogeneous distribution, and prevented the activation of NF‑κB. These results indicated that chronic low‑grade system inflammation may increase the inducibility of AF in a canine model. The underlying mechanism may be involved in the LPS‑induced activation of NF‑κB, and the increase in Cx43 expression and lateral distribution via an α1-AR-dependent pathway.

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