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Role of Paraoxonase in Diabetic Vascular Complications by Oxidative Stress

对氧磷酶在氧化应激引起的糖尿病血管并发症中的作用

基本信息

批准号：
11671125
负责人：
SUEHIRO Tadashi
金额：
$ 2.3万
依托单位：
Kochi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671125/
关键词：
Paraoxonase Oxidized LDL Oxidative stress Diabetic vascular injury Transcription transcription factor Sp1 HDL 遺伝子多型

项目摘要

Human serum paraoxonase (PON1) inhibits the oxidation of low-density lipoprotein, suggesting that PON1 protects against atherosclerosis. Oxidative stress in diabetic condition is involved in developments of diabetic macro- and microangiopathy. We studied whether PON1 was involved in the development of diabetic vascular injury through the oxidative stress.Every enzyme activity of PON1, paraoxonase, arylesterase or diazoxonase, was decreased in patients with type 2 diabetes as compared with normal controls, which suggested that PON1 functions in diabetic patients were disturbed. We established an ELISA for PON1 concentrations and found that the level of PON1 in diabetic patients was not different from that in normal controls, which suggested that PON1 might be up-regulated in diabetes.We investigated the promoter region of PON1 gene and found a novel polymorphism -108C/T, which influenced the transcription activity of PON1 and the serum concentrations. Further investigation of promoter region using reporter gene assay showed the PON1 transcription activity was suppressed by IL-1 and promoted by IL-6. Stimulation of oxidized LDL suppressed the PON1 transcription activity in early phase, but promoted in late phase. We also proved that Sp1 transcription factor played an important role in the PON1 transcription.The results suggested that the ability of PON1 which inhibited against oxidation were disturbed in diabetic patients, which was involved in the diabetic angiopathy, and oxidative stress in diabetes affects the PON1 transcription.

人血清对氧磷酶（PON 1）抑制低密度脂蛋白的氧化，表明PON 1对动脉粥样硬化具有保护作用。糖尿病状态下的氧化应激参与了糖尿病大血管和微血管病变的发展。我们研究了PON 1是否通过氧化应激参与了糖尿病血管损伤的发生发展，发现2型糖尿病患者PON 1的对氧磷酶、芳基酯酶和二氮氧磷酶的活性均较正常对照组降低，提示糖尿病患者PON 1的功能受到了干扰。我们建立了检测糖尿病患者血清中PON 1水平的ELISA方法，发现糖尿病患者血清中PON 1水平与正常对照组无明显差异，提示糖尿病患者PON 1水平可能上调，我们对PON 1基因启动子区进行了研究，发现了一个新的多态性-108C/T，该多态性影响PON 1的转录活性和血药浓度。通过报告基因分析进一步研究了PON 1的启动子区，发现IL-1抑制PON 1的转录活性，而IL-6促进PON 1的转录活性。氧化型LDL刺激后，PON 1的转录活性在早期受到抑制，而在晚期受到促进。结果表明，糖尿病患者PON 1抗氧化能力受到干扰，参与糖尿病血管病变的发生，糖尿病时氧化应激影响PON 1的转录。