Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology
Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology
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DOI：
10.1046/j.1440-1681.2003.03929.x
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发表时间：
2003-11-01
影响因子：
2.9
通讯作者：
Drummond, GR
中科院分区：
文献类型：
--
作者：
Bengtsson, SH;Gulluyan, LM;Drummond, GR
1.血管细胞已经进化到使用活性氧（ROS），例如超氧化物和过氧化氢，作为信号分子。在生理条件下，ROS是细胞周期、蛋白激酶活性和基因表达的重要调节因子。然而，在血管疾病状态下，如高血压和高胆固醇血症，ROS的过度产生可能会压倒细胞的抗氧化防御机制，导致“氧化应激”，损伤动脉壁，并最终发展为动脉粥样硬化斑块。血管系统中ROS的主要来源是NADPH氧化酶。似乎有至少三种同工型的NADPH氧化酶在血管壁中表达，每一个不同的关于黄素的催化亚基，它用来将电子从NADPH分子氧。因此，尽管内皮细胞和外膜成纤维细胞表达类似于最初在吞噬细胞中鉴定的含有gp 91 phox的NADPH氧化酶，但血管平滑肌细胞可能依赖于gp 91 phox的新同源物，即Nox 1和Nox 4来产生超氧化物。对于NADPH氧化酶的哪种亚型负责与血管疾病相关的氧化应激，仍存在争议。我们和其他人已经表明，虽然gp 91 phox mRNA的表达在人类和动物模型中动脉粥样硬化形成过程中上调，但Nox 4亚基的表达保持不变。Nox 1的表达也可能在患病动脉中增加;然而，其相对表达水平，至少在mRNA水平上，似乎明显低于其他gp 91 phox同源物，即使在上调后。这些研究结果是否表明，gp 91 phox含有NADPH氧化酶是更重要的是比Nox 4或Nox 1在血管疾病等待研究检查相对蛋白质表达和酶动力学的每个亚基，以及这些gp 91 phox同源物的靶向基因缺失对动脉粥样硬化的影响。
1. Vascular cells have evolved to use reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, as signalling molecules. Under physiological conditions, ROS are important regulators of cell cycle, protein kinase activity and gene expression. However, in vascular disease states, such as hypertension and hypercholesterolaemia, excessive production of ROS may overwhelm the anti-oxidant defence mechanisms of cells, resulting in 'oxidative stress', damage to the artery wall and, ultimately, development of atherosclerotic plaques.2. The primary source of ROS in the vasculature is NADPH oxidase. There appear to be at least three isoforms of NADPH oxidase expressed in the vascular wall, each differing with respect to the flavin-containing catalytic subunit it uses to transfer electrons from NADPH to molecular oxygen. Thus, although endothelial cells and adventitial fibroblasts express a gp91phox-containing NADPH oxidase similar to that originally identified in phagocytes, vascular smooth muscle cells may rely on novel homologues of gp91phox, namely Nox1 and Nox4, to produce superoxide.3. Controversy remains over which isoform(s) of NADPH oxidase is responsible for the oxidative stress associated with vascular diseases. We and others have shown that although gp91phox mRNA expression is upregulated during atherogenesis in human and animal models, expression of the Nox4 subunit remains unchanged. Nox1 expression is also likely to be increased in diseased arteries; however, its relative level of expression, at least at the mRNA level, appears to be markedly lower than that of the other gp91phox homologues, even after upregulation.4. Whether these findings suggest that a gp91phox-containing NADPH oxidase is more important than either Nox4 or Nox1 in vascular disease awaits studies examining relative protein expression and enzyme kinetics of each subunit, as well as the effects of targeted gene deletion of each of these gp91phox homologues on atherogenesis.