|Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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.