The Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Axis Protects Against Lung Fibroblast Migration and Lung Fibrosis by Inhibiting the NOX4-Derived ROS-Mediated RhoA/Rho Kinase Pathway
The Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Axis Protects Against Lung Fibroblast Migration and Lung Fibrosis by Inhibiting the NOX4-Derived ROS-Mediated RhoA/Rho Kinase Pathway
复制标题
血管紧张素转换酶 2/血管紧张素 (1-7)/Mas 轴通过抑制 NOX4 衍生的 ROS 介导的 RhoA/Rho 激酶途径，防止肺成纤维细胞迁移和肺纤维化
DOI：
10.1089/ars.2013.5818
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发表时间：
2015-01-20
影响因子：
6.6
通讯作者：
Li, Xu
中科院分区：
文献类型：
--
作者：
Meng, Ying;Li, Ting;Li, Xu
NADPH 氧化酶 4 (NOX4) 产生的活性氧 (ROS) 已被证明可引发肺纤维化。肺成纤维细胞迁移至损伤区域是肺纤维化的关键早期步骤。血管紧张素转换酶 2 (ACE2)/血管紧张素 (1-7) [Ang(1-7)]/Mas 轴可抵消 ACE/血管紧张素 II (AngII)/血管紧张素 II 1 型受体 (AT1R) 轴，已被证明可以减轻肺纤维化。然而，确切的分子机制仍不清楚。目的：通过调节 NOX4 衍生的 ROS 介导的 RhoA/Rho 激酶 (Rock) 通路，研究肾素-血管紧张素系统 (RAS) 两个轴对肺成纤维细胞迁移和细胞外基质积累的不同影响。结果：在体外，AngII 显着增加肺成纤维细胞中 NOX4 水平和 ROS 产生，从而通过 RhoA/Rock 途径刺激细胞迁移和 α-胶原蛋白 I 合成。 N-乙酰半胱氨酸 (NAC)、二亚苯基碘鎓和 NOX4 RNA 干扰可减弱这些作用。此外，Ang(1-7) 和慢病毒介导的 ACE2 (lentiACE2) 通过抑制 NOX4 衍生的 ROS 介导的 RhoA/Rock 通路，抑制 AngII 诱导的迁移和 α-胶原蛋白 I 合成。然而，Ang(1-7)单独对AngII产生类似的作用。在体内，持续输注Ang（1-7）或气管内滴注lenti-ACE2可将RAS平衡转向ACE2/Ang（1-7）/Mas轴，减轻博莱霉素诱导的肺纤维化，并通过减少NOX4衍生的ROS来抑制RhoA/Rock通路。创新：本研究表明，新的药理学抗氧化策略可能以 ACE2/Ang(1-7)/Mas 轴为目标，治疗 AngII 介导的 ROS 诱导的肺纤维化。结论：ACE2/Ang(1-7)/Mas 轴通过抑制 NOX4 衍生的 ROS 介导的 RhoA/Rock 通路来防止肺成纤维细胞迁移和肺纤维化。抗氧化剂。氧化还原信号。 22、241-258。
Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. Aims: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. Results: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and alpha-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and alpha-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. Innovation: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. Conclusion: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. Antioxid. Redox Signal. 22, 241-258.