The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling.
The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling.
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Rho/ROCK 通路在 Ang II 和 TGF-β1 诱导的心房重塑中的作用
DOI：
10.1371/journal.pone.0161625
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wu SH
中科院分区：
文献类型：
--
作者：
Liu LJ;Yao FJ;Lu GH;Xu CG;Xu Z;Tang K;Cheng YJ;Gao XR;Wu SH
探讨Rho/ROCK通路在Ang Ⅱ和TGF-β1诱导的心房重构中的作用。采用快速心房起搏（RAP）方法建立犬心房颤动（AF）模型。通过体外和体内实验研究了TGF-β1、RhoA/ROCK信号通路和结缔组织生长因子（CTGF）在心房重构中的作用。每只接受RAP的狗在4周内都出现了持续性AF。RAP 4周后，左心房TGF-β1（1.32±0.38）、Collagen-I（1.33±0.91）、CTGF（5.83±3.71）、RhoA（1.23±0.57）和ROCK-1（1.02±0.27）的mRNA表达水平显著升高。血管紧张素II（Ang II）可诱导心房成纤维细胞增殖，并以剂量依赖方式上调CTGF和ROCK-1的表达。辛伐他汀和Y27632逆转Ang II诱导的CFs增殖，以及ROCK-1（分别为0.89±0.05和1.27±0.03）和CTGF（分别为0.87±0.04和0.91±0.02）的表达。TGF-β1可上调ROCK-1（1.74±0.13）和CTGF（2.28±0.11）的mRNA表达，而辛伐他汀（1.22±0.03 vs 2.27±0.11）、Y27632（1.01±0.04 vs 1.64±0.03）、Los（1.04±0.11 vs 1.26±0.05）可下调ROCK-1和CTGF的mRNA表达。Losartan和Simvastatin可减弱TGF-β1的作用，抑制RhoA活性，而不是RhoA蛋白表达。Y27632对RhoA的表达和活性均无影响。促纤维化因子（CTGF、ROCK 1和Smad 2/3）的表达增加在我们的RAP诱导的AF模型中起重要作用。增加的心房促纤维化因子涉及TGF-β1/RhoA/ROCK-1或TGF-β1/Smad 2/3信号通路的激活。
To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.
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