Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts
Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts
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DOI：
10.1016/j.yexcr.2012.06.015
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发表时间：
2012-10-01
影响因子：
3.7
通讯作者：
Zhou, Li
中科院分区：
文献类型：
--
作者：
Gu, Jun;Liu, Xu;Zhou, Li
血管紧张素II（AngII）诱导的转化生长因子β 1（TGF-β 1）/Smad信号通路的激活和结缔组织生长因子（CTGF）表达的增加被认为是心房纤维化的机制。然而，TGF β 1/非Smad信号通路是否参与AngII诱导的纤维化因子表达仍不清楚。最近，肿瘤坏死因子受体相关因子6（TRAF6）/TGF β相关激酶1（TAK1）已被证明对TGF β 1/非Smad信号通路的激活至关重要。在本研究中，我们探讨了TGF-β 1/TRAF6通路在血管紧张素II诱导的成人心房成纤维细胞CTGF表达中的作用。AngII（1 μ M）引起P38丝裂原活化蛋白激酶（P38 MAPK）、细胞外信号调节激酶1/2（ERK 1/2）和c-Jun NH（2）-末端激酶（JNK）的激活。AngII（1 μ M）还促进TGF β 1、TRAF 6、CTGF表达和TAK 1磷酸化，这些都被血管紧张素I型受体拮抗剂（Losartan）以及p38 MAPK抑制剂（SB202190）、ERK 1/2抑制剂（PD98059）和JNK抑制剂（SP600125）抑制。同时，TGF β 1抗体和TRAF6 siRNA均能降低Ang Ⅱ对TRAF6、CTGF表达和TAK1磷酸化的刺激作用，从而抑制Ang Ⅱ诱导的心房成纤维细胞增殖。总之，MAPKs/TGF β 1/TRAF6通路是AngII诱导的CTGF表达中的重要信号通路，因此TRAF6的抑制可能代表逆转AngII诱导的心房纤维化的新靶点。(C)2012 Elsevier Inc. All rights reserved.
The activation of transforming growth factor-beta 1(TGF-beta 1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF beta 1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF beta-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-beta 1/non-Smad signaling pathways. In the present study, we explored the role of TGF-beta 1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 mu M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 mu M) also promoted TGF beta 1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF beta 1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF beta 1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. (C) 2012 Elsevier Inc. All rights reserved.