摘要
Aims: We investigated the molecular mechanism of rapid-depolarization- induced atrial fibrosis. Methods and results: We used a direct atrial myocyte-fibroblast contact co-culture and a fibroblast-specific transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF) and procollagen type I α-1 (COL1A1) luciferase reporter system to investigate the possible molecular mechanism of rapid-depolarization-induced atrial fibrosis. Mouse atrial fibroblasts were first transfected with promoter-luciferase reporters, and then co-cultured with HL-1 atrial myocytes. Rapid depolarization of atrial myocytes by rapid electrical field stimulation induced increased TGF-β1, CTGF and COL1A1 promoter activities in the co-cultured atrial fibroblasts (2.4 ± 0.3-fold increase, P = 0.008 for TGF-β1; 2.9 ± 0.4-fold increase, P < 0.001 for CTGF; and 2.1 ± 0.2-fold increase, P = 0.008 for COL1A1). Rapid depolarization of atrial myocytes increased paracrine secretion of angiotensin II (Ang II) and reactive oxygen species in the co-culture medium. Rapid electrical field stimulation-induced ROS generation in atrial myocytes was attenuated by the membrane NADPH oxidase inhibitor, apocynin. Atrial myocyte-induced expression of TGF-β1, CTGF and COL1A1 in atrial fibroblasts was attenuated by co-treatment with the Ang II receptor blocker, losartan, and apocynin. Atrial myocyte-induced COL1A1 expression in atrial fibroblasts was attenuated by anti-TGF-β1 antibody and RNA interference knockdown of the TGF-β1 receptor. Conclusion: We first demonstrated that tachycardia of atrial myocytes induced paracrine secretion of Ang II and reactive oxygen species, which in turn induced expression of CTGF and procollagen in co-cultured atrial fibroblasts through increasing TGF-β1 expression. The results may imply that use of an Ang II receptor blocker, in combination with an anti-oxidant, blocks rapid-depolarization-induced atrial fibrosis. Published on behalf of the European Society of Cardiology. All rights reserved.
原文 | 英語 |
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頁(從 - 到) | 805-815 |
頁數 | 11 |
期刊 | Cardiovascular Research |
卷 | 89 |
發行號 | 4 |
DOIs | |
出版狀態 | 已發佈 - 3月 1 2011 |
對外發佈 | 是 |
ASJC Scopus subject areas
- 心臟病學與心血管醫學
- 生理學(醫學)
- 生理學