Role of Paraoxonase in Diabetic Vascular Complications by Oxidative Stress

人血清对氧磷酶（PON1）抑制低密度脂蛋白的氧化，提示PON1对动脉粥样硬化具有保护作用。糖尿病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PON1是否通过氧化应激参与糖尿病血管损伤的发生。与正常对照相比，2型糖尿病患者PON1对氧磷酶、芳基酯酶、重氮磷酶的各项酶活性均下降，提示糖尿病患者PON1功能受到干扰。我们建立了PON1浓度的ELISA检测，发现糖尿病患者的PON1水平与正常对照无明显差异，提示PON1可能在糖尿病中上调。我们研究了PON1基因的启动子区域，发现了一个新的多态性-108C/T，该多态性影响PON1的转录活性和血清浓度。进一步利用报告基因检测对启动子区域的研究表明，PON1的转录活性被IL-1抑制，而被IL-6促进。刺激氧化LDL在早期抑制PON1转录活性，但在后期促进。我们也证实Sp1转录因子在PON1转录中发挥重要作用。提示糖尿病患者PON1抗氧化能力受到干扰，参与糖尿病血管病变，糖尿病氧化应激影响PON1的转录。

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.