Role of Paraoxonase in Diabetic Vascular Complications by Oxidative Stress

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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.