*Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
Clin Sci (Lond). 2014 Aug;127(4):251-64. doi: 10.1042/CS20130585.
AngII (angiotensin II) induces pathological conditions such as fibrosis in skeletal muscle. In this process, AngII increases ROS (reactive oxygen species) and induces a biphasic phosphorylation of p38 MAPK (mitogen-activated protein kinase). In addition, AngII stimulates the expression and production of TGF (transforming growth factor)-β1 via a mechanism dependent on ROS production mediated by NADPH oxidase (NOX) and p38 MAPK activation. In the present study, we investigated whether Ang-(1-7) [angiotensin-(1-7)], through the Mas-1 receptor, can counteract the signalling induced by AngII in mouse skeletal muscle and cause a decrease in the expression and further activity of TGF-β1 in skeletal muscle cells. Our results show that Ang-(1-7) decreased the expression of TGF-β1 induced by AngII in a dose-dependent manner. In addition, we observed that Ang-(1-7) prevented the increase in TGF-β1 expression induced by AngII, ROS production dependent on NOX and the early phase of p38 MAPK phosphorylation. Interestingly, Ang-(1-7) also prevented the late phase of p38 MAPK phosphorylation, Smad-2 phosphorylation and Smad-4 nuclear translocation, an increase in transcriptional activity, as determined using the p3TP-lux reporter, and fibronectin levels, all of which are dependent on the TGF-β1 levels induced by AngII. We also demonstrated that Ang-(1-7) prevented the increase in TGF-β1, fibronectin and collagen content in the diaphragm of mice infused with AngII. All of these effects were reversed by the administration of A779, indicating the participation of Mas-1. In conclusion, our findings support the hypothesis that Ang-(1-7) decreases the expression and further biological activity of TGF-β1 induced by AngII in vitro and in vivo.
血管紧张素 II（angiotensin II）可诱导纤维化等病理状况发生在骨骼肌中。在这个过程中，血管紧张素 II 会增加 ROS（活性氧）并诱导 p38 MAPK（丝裂原激活蛋白激酶）的两相磷酸化。此外，血管紧张素 II 通过依赖 NADPH 氧化酶（NOX）产生的 ROS 介导的机制和 p38 MAPK 激活来刺激 TGF-β1 的表达和产生。在本研究中，我们研究了血管紧张素-(1-7) [血管紧张素-(1-7)] 是否可以通过 Mas-1 受体拮抗血管紧张素 II 在小鼠骨骼肌中的信号传导，并导致 TGF-β1 在骨骼肌细胞中的表达和进一步活性降低。我们的结果表明，血管紧张素-(1-7) 以剂量依赖的方式降低了血管紧张素 II 诱导的 TGF-β1 的表达。此外，我们观察到血管紧张素-(1-7) 阻止了血管紧张素 II 诱导的 TGF-β1 表达增加、依赖于 NOX 的 ROS 产生以及 p38 MAPK 磷酸化的早期阶段。有趣的是，血管紧张素-(1-7) 还阻止了 p38 MAPK 磷酸化的晚期阶段、Smad-2 磷酸化和 Smad-4 核易位、转录活性的增加，如使用 p3TP-lux 报告基因测定，以及纤维连接蛋白水平，所有这些都依赖于血管紧张素 II 诱导的 TGF-β1 水平。我们还证明了血管紧张素-(1-7) 可防止在 AngII 输注的小鼠膈肌中 TGF-β1、纤维连接蛋白和胶原蛋白含量的增加。所有这些作用都被 A779 的给药逆转，表明 Mas-1 的参与。总之，我们的研究结果支持了这样一种假设，即血管紧张素-(1-7) 降低了体外和体内血管紧张素 II 诱导的 TGF-β1 的表达和进一步的生物学活性。
