Liang Mingyu, Pietrusz Jennifer L
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):77-83. doi: 10.1161/01.ATV.0000251006.54632.bb. Epub 2006 Oct 26.
Our laboratory and others have found that deficiencies in cellular thiols may be importantly involved in the development of diabetic complications. However, the role for specific thiol-related genes in diabetic complications is unclear.
We began the present study by systematically determining the expression level of 11 thiol-related genes in three tissues from rats with streptozotocin-induced diabetes. Several thiol-related genes were found to exhibit diabetes-associated, time-dependent differential expression. Thioredoxin 2, a mitochondrion-specific thioredoxin whose role in diabetes was unknown, was suppressed in the aorta from rats with two weeks of diabetes. When thioredoxin 2 expression in human umbilical vein endothelial cells was knocked-down by small interfering RNA, high-ambient glucose-elicited substantial injurious effects (n=5 to 9, P<0.05), including increases in cytosolic cytochrome c (by 2.2+/-0.6-fold), lipid peroxidation (by 40+/-8%), fibronectin expression (by 35+/-7%), and oxidized glutathione, and decreases in endothelial nitric oxide synthase expression (by 79+/-15%), basal accumulation of nitrite/nitrate (by 68+/-16%), total free thiols (by 42+/-8%), and glutathione (by 6+/-1%). In the absence of thioredoxin 2 knockdown, high-ambient glucose did not have significant effects on any of these measurements. The effect of thioredoxin 2 knockdown appeared to be associated with increases in glucose consumption and glucose transporter 1 expression.
These results provided the first expression profile of thiol-related genes in a model of diabetes and demonstrated a novel role for endogenous thioredoxin 2 in protecting cells against high ambient glucose.
我们实验室及其他研究发现，细胞内硫醇缺乏可能在糖尿病并发症的发生发展中起重要作用。然而，特定硫醇相关基因在糖尿病并发症中的作用尚不清楚。
我们通过系统测定链脲佐菌素诱导糖尿病大鼠三种组织中11个硫醇相关基因的表达水平，开展了本研究。发现几个硫醇相关基因呈现出与糖尿病相关的、时间依赖性的差异表达。硫氧还蛋白2是一种线粒体特异性硫氧还蛋白，其在糖尿病中的作用未知，在糖尿病两周的大鼠主动脉中表达受到抑制。当用小干扰RNA敲低人脐静脉内皮细胞中的硫氧还蛋白2表达时，高环境葡萄糖引发了显著的损伤效应（n = 5至9，P < 0.05），包括胞质细胞色素c增加（2.2±0.6倍）、脂质过氧化增加（40±8%）、纤连蛋白表达增加（35±7%）以及氧化型谷胱甘肽增加，同时内皮型一氧化氮合酶表达减少（79±15%）、亚硝酸盐/硝酸盐基础积累减少（68±16%）、总游离硫醇减少（42±8%）以及谷胱甘肽减少（6±1%）。在未敲低硫氧还蛋白2的情况下，高环境葡萄糖对这些测量指标均无显著影响。硫氧还蛋白2敲低的效应似乎与葡萄糖消耗增加和葡萄糖转运蛋白1表达增加有关。
这些结果提供了糖尿病模型中硫醇相关基因的首个表达谱，并证明了内源性硫氧还蛋白2在保护细胞免受高环境葡萄糖损伤方面的新作用。
