The NOX-ROS connection: targeting Nox1 control of N-cadherin shedding in vascular smooth muscle cells.
The NOX-ROS connection: targeting Nox1 control of N-cadherin shedding in vascular smooth muscle cells.
复制标题
NOX-ROS 连接：靶向 Nox1 控制血管平滑肌细胞中 N-钙粘蛋白的脱落。
DOI：
10.1093/cvr/cvs020
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发表时间：
2012
影响因子：
10.8
通讯作者：
Cahill,PaulA
中科院分区：
文献类型：
--
作者：
Redmond,EileenM;Cahill,PaulA
The Nox family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is an important source of reactive oxygen species (ROS). They comprise a group of transmembrane proteins possessing six transmembrane domains with conserved binding sites for FAD and NADPH and four haem-binding histidines in the third and fifth transmembrane domains whose function is to produce ROS by transferring an electron to molecular oxygen. This process yields superoxide anions (O2 J), which can further react to hydrogen peroxide (H2O2) or, in the presence of nitric oxide (NO), to peroxynitrite (ONOOJ). Although ROS can be highly reactive and oxidize proteins, DNA, and lipids, they are now considered important signalling molecules in their own right, modulating cellular processes such as gene expression, proliferation, and migration. 1 NADPH oxidases are critical determinants of the redox status of the vessel wall and are important in the pathophysiology of atherosclerosis. 1 In vascular cells, the NADPH oxidase isoforms Nox1, Nox2, Nox4, and Nox5 are expressed and differ in their activity, response to stimuli, and the type of ROS released. 1 Much attention has focused on the roles of different Nox isoforms in ROS generation in vascular smooth muscle cells (VSMC) and the resulting changes in phenotype and fate. 1 However, the intracellular signalling events by which NADPH oxidase-generated ROS modulate VSMC function and atherogenesis have yet to be elucidated. In this context, Jagadeesha et al. 2 demonstrate for the first time that Nox1 NADPH oxidase transduces its signal in VSMC through a novel c-Src-mediated transactivation of the epidermal growth factor receptor (EGFR) to activate matrix metalloproteinase 9 (MMP-9) and promote VSMC migration in vitro. Previous studies had linked Nox1 to VSMC phenotypic changes, including angiotensin II-induced hypertrophy, 3 serum-induced proliferation, 4 and basic fibroblast growth factor (bFGF)-induced migration. 5 In addition, Nox1-derived ROS may participate in neointimal formation by mediating PDGF-induced signalling. 6 Jagadeesha et al. 2 further addressed the potential involvement of thrombin-induced, NADPH oxidase-induced ROS and downstream cell–cell adhesion by the cadherin: catenin complex 7 in the regulation of VSMC behaviour, using multiple approaches to modify the expression of Nox1 in VSMC. Their data clearly identify steps in the signalling cascade by which Nox1-dependent ROS generation contributes to VSMC migration in vitro. These steps include (i) Nox1-dependent transactivation of EGFR via c-Src;(ii) transactivation of EGFR leading to ERK1/2 phosphorylation;(iii) Nox1-dependent EGFR transactivation leading to MMP-9 activation via ERK1/2 phosphorylation, and (iv) Nox1/EGFR/MMP-9-induced N-cadherin shedding. As arterial injury and atherosclerotic lesions are characterized by enhanced thrombin expression and activity, increased Nox activity, and increased ROS production, 8 activation of this signalling cascade by thrombin identifies one potential mechanism by which Nox1-derived ROS may promote intimal vascular disease. Because others have delineated many of the growth-related signalling pathways associated with Nox1, the study by Jagadeesha et al. 2 focused primarily on understanding the mechanisms by which Nox1 regulates VSMC migration. Changes in N-cadherin-mediated cell–cell adhesion and intimal thickening have already been shown to involve matrix-degrading MMP-dependent shedding of the extracellular portion of N-cadherin, leading to increased VSMC proliferation via elevation of b-catenin signalling and cyclin D1 …
