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

高血糖和动脉粥样硬化：内皮细胞中自由基清除功能障碍和异常基因表达

基本信息

批准号：
05670854
负责人：
KASHIWAGI Atsunori
金额：
$ 1.34万
依托单位：
SHIGA UNIVERSITY OF MEDICAL SCIENCE
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

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

众所周知，血管细胞中活性氧自由基的异常产生和降解是导致衰老和糖尿病加速动脉粥样硬化的主要因素。特别是，我们已经表明，暴露于高葡萄糖条件的培养内皮细胞中自由基清除剂功能受损。此外，高葡萄糖条件下氧化应激的增加可以诱导内皮细胞基因表达的激活。本研究中研究了以下血管内皮细胞功能障碍。1）暴露于高葡萄糖培养基的内皮细胞中戊糖磷酸途径的激活受损和谷胱甘肽氧化还原（GR）循环功能障碍。我们报道，暴露于高葡萄糖培养基的内皮细胞中GR循环减少了50%（Kashiwagi et al Diabetes 1992，柏木等人。糖尿病学 1994，Asahina 等人。糖尿病 1995）。这些异常的 GR 循环也在酸中毒中发现（Ikebuchi 等人代谢，1993），并通过自由基清除剂（Kashiwagi 等人糖尿病 1991,1991）或丙酮酸治疗内皮细胞（Kashiwagi 等人 Am J Physiol. 提交中）来逆转。2）高葡萄糖条件下的内皮细胞活化特定内皮细胞中的 ICAM-1 表达以高葡萄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是通过高渗效应介导的，而不是由氧化应激介导的。 3）氧化LDL和溶血磷脂酰胆碱与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 提交）。这种效应是由 PKC 激活介导的。[总结]糖尿病的代谢异常（高血糖、高渗透压、酸中毒、脂质氧化）可对内皮细胞的各种基因表达产生深远的影响，这表明内皮细胞的激活导致单核细胞和内皮细胞之间的相互作用加速。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。为了防止血管组织老化和动脉粥样硬化，利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项目。较少的