Regulation of Gene Expression of Antioxidative Enzymes in Vascular Cells and their Gene Transfer

氧化应激与多种血管疾病的发病机制有关。氧化还原状态被精细地调整以通过氧化剂和抗氧化酶的表达和调节来保持细胞内稳态。哺乳动物细胞内存在复杂的抗氧化剂网络，如过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶（GPX），除此之外，巯基二硫化物氧化还原酶家族成员如谷氧还蛋白（GRX）和硫氧还蛋白（TRX）也可作为细胞保护性抗氧化剂。因此，我们研究了剪切力对培养的内皮细胞GPX表达的影响。层流剪切力以时间和力依赖的方式上调GPX的表达。另一方面，TNF增加培养的冠状动脉平滑肌细胞中TRX/GRX的表达。因此，局部因素，如细胞因子和血流动力学力调节抗氧化酶在血管cells.Next的表达，我们研究了抗氧化酶在人体冠状动脉使用尸检样本的表达。在正常冠状动脉中，TRX/GRX表达于内皮、外膜和中膜SMC，GPx主要表达于内皮。在动脉粥样硬化病变中，GPx和TRX/GRX通过血管壁上调，而Cu/Zn SOD没有如此变化。特别是新生内膜中的巨噬细胞高表达TRX/GRX。鉴于氧化应激的重要性，利用基因转移调节抗氧化酶可能是抗动脉粥样硬化的一种可能的治疗工具。

Oxidative stress is implicated in the pathogenesis of a variety of vascular diseases. Redox State is finely tuned to preserve cellular homeostasis through the expression and regulation of oxidant and antioxidant enzymes. Mammalian cells have a complex network of antioxidants such as catalase, superoxide dismutase, and glutathione peroxidase (GPX) to scavenge ROS.In addition to these enzymes, the members of a family of thiol-distulfide oxidoreductases such as glutaredoxin (GRX) and thioredoxin (TRX) act as cytoprotective antioxidants.Shear stress and stretch force have profound effect on the gene expression. Therefore, we investigated effects of shear stress on the expression of GPX in cultured endothelial cells. Laminar fluid shear stress upregulated the expression of GPX in time- and force-dependent manner. On the other hand, TNF increased the expression of TRX/GRX in cultured coronary artery smooth muscle cells. Thus, local factors such as cytokines and hemodynamic force regulate the expression of antioxidative enzymes in vascular cells.Next, we investigated the expression of antioxidant enzymes in human coronary arteries using autopsied samples. In normal coronary arteries, TRX/GRX was expressed at endothelium, adventitia, and intensively in medial SMC.GPx was expressed mainly in endothelium. In atherosclerotic lesions, GPx and TRX/GRX were upregulated through vessel walls, whereas Cu/Zn SOD was not so changed. Especially, macrophages in neointima highly expressed TRX/GRX.Given the importance of oxidative stress, the modulation of antioxidative enzymes using gene transfer could be a possible therapeutic tool against atherosclerosis.