Tachycardia of atrial myocytes induces collagen expression in atrial fibroblasts through transforming growth factor β1
Tachycardia of atrial myocytes induces collagen expression in atrial fibroblasts through transforming growth factor β1
复制标题
DOI：
10.1093/cvr/cvq322
复制
发表时间：
2011-03-01
影响因子：
10.8
通讯作者：
Lin, Jiunn-Lee
中科院分区：
文献类型：
--
作者：
Tsai, Chia-Ti;Tseng, Chuen-Den;Lin, Jiunn-Lee
目的探讨快速去极化诱导心房纤维化的分子机制。方法与结果采用直接接触培养的心房肌细胞与成纤维细胞特异性转化生长因子-β1、结缔组织生长因子和I型前胶原α-1(COL1A1)荧光素酶报告系统，探讨快速去极化诱导心房纤维化的可能分子机制。首先将启动子-荧光素酶报告基因导入小鼠心房成纤维细胞，然后与HL-1心房肌细胞共培养。快速电场刺激引起的心房成纤维细胞的快速去极化使共培养的心房成纤维细胞中转化生长因子-β1、结缔组织生长因子和COL1A1启动子活性增加(转化生长因子-β1增加2.4+/-0.3倍，P=0.008；结缔组织生长因子增加2.9+/-0.4倍，P=0.001；COL1A1增加2.1+/-0.2倍，P=0.008)。心房肌细胞快速去极化后，共培养上清液中血管紧张素II(Ang II)和活性氧的旁分泌增加。膜NADPH氧化酶抑制剂apocynin可减弱电场刺激诱导的心房肌细胞ROS生成。Ang II受体阻滞剂氯沙坦和载脂蛋白A共同处理可减弱心房肌细胞诱导的转化生长因子-β1、结缔组织生长因子和COL1A1的表达。抗转化生长因子-β1抗体和RNA干扰敲除转化生长因子-β1受体可抑制心房成纤维细胞COL1A1的表达。结论我们首次证实心房肌细胞心动过速可诱导血管紧张素Ⅱ和活性氧的旁分泌，进而通过增加转化生长因子-β1的表达诱导共培养的心房成纤维细胞CTGF和前胶原的表达。这一结果可能暗示血管紧张素II受体阻滞剂与抗氧化剂联合使用，可阻断快速去极化诱导的心房纤维化。
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 beta 1 (TGF-beta 1), connective tissue growth factor (CTGF) and procollagen type I alpha-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-beta 1, CTGF and COL1A1 promoter activities in the co-cultured atrial fibroblasts (2.4 +/- 0.3-fold increase, P = 0.008 for TGF-beta 1; 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-beta 1, 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-beta 1 antibody and RNA interference knockdown of the TGF-beta 1 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-beta 1 expression. The results may imply that use of an Ang II receptor blocker, in combination with an antioxidant, blocks rapid-depolarization-induced atrial fibrosis.