Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells
Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells
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DOI：
10.1016/j.bbrc.2011.06.051
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发表时间：
2011-07-08
影响因子：
3.1
通讯作者：
Brandan, Enrique
中科院分区：
文献类型：
--
作者：
Cabello-Verrugio, Claudio;Jose Acuna, Maria;Brandan, Enrique
纤维性疾病的典型特征是结缔组织过度结缔组织和细胞外基质(ECM)沉积，这阻碍了不同组织的正常愈合过程。血管紧张素-II(Ang-II)参与了纤维化反应。几种肌营养不良症的特点是广泛的纤维化。然而，Ang-II在骨骼肌纤维化中的确切作用尚不清楚。在此，我们发现成肌细胞对Ang-II的反应是通过增加结缔组织生长因子(CTGF/CCN2)、Ⅲ型胶原和纤维连接蛋白的蛋白水平来实现的。这些Ang-II诱导的促纤维化作用是由AT-1受体介导的。值得注意的是，Ang-II通过NAD(P)H氧化酶依赖的机制诱导活性氧(ROS)，表现为通过NAD(P)H氧化酶抑制剂DPI和apocynin抑制ROS的产生。这种ROS的增加对Ang-II诱导的纤维化效应至关重要，DPI和apocynin降低了Ang-II诱导的CTGF和纤维连接蛋白水平。我们还发现，Ang-II诱导的ROS的产生和纤维化需要PKC的活性，这一结果强烈表明Ang-II诱导的纤维化反应是由AT-I受体介导的，需要NAD(P)H诱导的骨骼肌细胞ROS。(C)2011 Elsevier Inc.保留所有权利。
Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes in different tissues. Angiotensin-II (Ang-II) is involved in the fibrotic response. Several muscular dystrophies are characterized by extensive fibrosis. However, the exact role of Ang-II in skeletal muscle fibrosis is unknown. Here we show that myoblasts responded to Ang-II by increasing protein levels of connective tissue growth factor (CTGF/CCN2), collagen-III and fibronectin. These Ang-II-induced pro-fibrotic effects were mediated by AT-1 receptors. Remarkably, Ang-II induced reactive oxygen species (ROS) via a NAD(P)H oxidase-dependent mechanism, as shown by inhibition of ROS production via the NAD(P)H oxidase inhibitors diphenylene iodonium (DPI) and apocynin. This increase in ROS is critical for Ang-II-induced fibrotic effects, as indicated by the decrease in Ang-II-induced CTGF and fibronectin levels by DPI and apocynin. We also show that Ang-II-induced ROS production and fibrosis require PKC activity as indicated by the generic PKC inhibitor chelerythrine.These results strongly suggest that the fibrotic response induced by Ang-II is mediated by AT-I receptor and requires NAD(P)H-induced ROS in skeletal muscle cells. (C) 2011 Elsevier Inc. All rights reserved.