Hyperglycemia and atherosclerosis : Radical scavenger dysfunction and abnormal gene expression in endothelial cells

血管细胞活性氧自由基的异常产生和降解是导致老年人和糖尿病患者动脉粥样硬化加速的重要因素。特别是，我们已经表明，自由基清除功能受损，在培养的内皮细胞暴露于高糖条件。此外，高糖条件下增加的氧化应激可诱导内皮细胞基因表达的激活。本实验研究了高糖对血管内皮细胞功能的影响：1）高糖对内皮细胞磷酸戊糖途径的激活和谷胱甘肽氧化还原（GR）循环的影响，高糖使GR循环减少50（Kashiwagi等Diabetes 1992，Kashiwagi等Diabetologia 1994，Asahina等Diabetes 1995）。这些异常的GR周期也见于酸中毒（Ikebuchi et al Metabolism，1993）， ...更多信息 通过自由基清除剂的处理，（Kashiwagi等人，Diabetes 1991，1991）或丙酮酸对内皮细胞（Kashiwagi等，Am J Physiol.in submission）。2）高糖条件下的内皮细胞活化内皮细胞中的特异性ICAM-1表达以高糖特异性和浓度依赖性方式被诱导，并导致单核细胞与内皮细胞的粘附增加（Taki等人提交的动脉粥样硬化）。高糖条件下内皮细胞功能的激活通过高渗效应介导，而不是通过氧化应激介导。3）氧化LDL和溶血磷脂酰胆碱和内皮细胞基因表达氧化LDL和主要成分溶血磷脂酰胆碱（LPC）可以诱导内皮细胞中MCP-1基因表达（Takahara等，Metabolism，in submission）。这种作用是通过激活PKC介导的。[In糖尿病中的代谢异常（高血糖、高渗、酸中毒、脂质氧化）可诱导对内皮细胞的各种基因表达的深刻影响，这表明内皮细胞的活化导致单核细胞和内皮细胞之间的加速相互作用。这种相互作用可能是糖尿病早期动脉粥样硬化形成的初始事件。为预防血管组织老化和动脉粥样硬化，应用抗氧化药物预防糖尿病体内氧化应激的临床研究将是未来的研究项目。少

It has been well known that abnormal production and degradation of active oxygen radicals in vascular cells are major factors which can induce accelerated atherosclerosis in aging and diabetes mellitus. Particularly, we have shown that radical scavenger function is impaired in cultured endothelial cells exposed to high glucose condition. Furthermore, the increased oxidative stress in high glucose condition can induce activation of endothelial cell gene expression. The following vascular endothelial cell dysfunction was studied in the present study.1) Impaired activation of pentose phosphate pathway and dysfunction of glutathione redox (GR) cycle in endothelial cells exposed to high glucose medium.We reported that GR cycle was dccreased by 50% in endothelial cells exposed to high glucose medium (Kashiwagi et al Diabetes 1992, Kashiwagi et al. Diabetologia 1994, Asahina et al. Diabetes 1995). These abnormal GR cycle was also found in acidosis (Ikebuchi et al Metabolism, 1993) and was rev … More ersed by the treatment of either radical scavenger (Kashiwagi et al. Diabetes 1991,1991) or pyruvate to endothelial cells (Kashiwagi et al. Am J Physiol. in submission).2) Endothelial cell activation in high glucose conditionSpecific ICAM-1 expression in endothelial cells was induced as high glucose-specific and concentration-dependent manners and resulted in increased adhesion of monocytes to endothelial cells (Taki et al. Atheroscleresis in submission). The activation of endothelial cell function in high glucose condition was mediated via hyperosmolar effect and was not mediated by oxidative stress.3) Oxidized LDL and Lysophosphatidylcholine and endothelial cell gene expressionOxidized LDL and a main component lysophosphatidylcholine (LPC) can induce MCP-1 gene expression in endothelial cells (Takahara et al, Metabolism, in submission). This effect was mediated by activation of PKC.[In summary] Metabolic abnormalities in diabetes (hyperglycemia, hyperosmolarity, acidosis, lipid oxidation) can induce profound effects on various gene expression of endothelial cells which indicate activation of endothelial cells resulting in accelerated interaction between monocytes and endothelial cells. The interaction may be an initial event of early atherogenesis in diabetes. To prevent aging of vascular tissue and atherosclerosis, clinical studies to prevent in vivo oxidative stress in diabetes using antioxidant drugs will be the future projects. Less