OXIDATIVE STRESS AND ATHEROSCLEROTIC COMPLICATIONS OF DIABETES

糖尿病的氧化应激和动脉粥样硬化并发症

• 批准号: 6303355
• 负责人: FRANCESCA CATELLA-LAWSON
• 金额: $ 2.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6303355
• 关键词: ascorbate; atherosclerosis; clinical research; copper; diabetes mellitus; diabetic angiopathy; eicosanoids; free radicals; gas chromatography mass spectrometry; glycosylation; human subject; low density lipoprotein; medical complication; molecular pathology; oxidative stress; tocopherols; urinalysis

The role of oxidative stress in the evolution of diabetic vascular complications is unclear, in part due to limitation of current methodology to assess free radical generation in vivo. The present study will utilize gas chromatography/mass spectrometry (GC/MS) methods for the measurement of two structurally distinct F2-isoprostanes, 8-epi-PGF2a-I. These novel markers of free radical catalyzed lipid peroxidation in vivo will be assessed in conjunction with LDL oxidizability and endothelial vasomotor function to address the hypothesis that oxidative stress is enhanced in diabetes mellitus and that this precedes the onset of micro or macrovascular disease. Urinary excretion of the F2-Isoprostanes will be measured in patients with type 1 diabetes with and without retinopathy; in patients with type 2 diabetes with and without macrovascular disease; in patients with peripheral vascular disease of non-diabetic origin and in appropriate controls. Because isoprostanes are formed in situ from arachidonic acid esterified to phospholipid, we will isolate LDL to measure the degree to which LDL phospholipids contain 8-epi-PGF2a and IPF2a-I. We will also assess the LDL susceptibility to oxidation and the time course of formation of F2-Isoprostanes in the LDL during copper-induced oxidation. Endothelial-dependent and endothelial-independent dilatation of the brachial artery will be measured by high-resolution, non-invasive vascular antioxidants, vitamins E+C, will depress urinary excretion of F2-Isoprostanes concomitantly with modulation of LDL susceptibility to oxidation and restoration of endothelial vasomotor function. The results of this study might support the hypothesis that increased oxidative stress in diabetes precedes the onset of vascular complications and might indicate a therapeutic role for antioxidants in complementing other therapeutic approaches to the prevention or amelioration of diabetic complications.

氧化应激在糖尿病血管并发症演变中的作用尚不清楚，部分原因是目前评估体内自由基生成的方法存在局限性。 本研究将利用气相色谱/质谱（GC/MS）方法测量两种结构不同的F2-异前列烷，8-epi-PGF 2a-I。这些新的自由基催化的脂质过氧化反应在体内的标志物将与LDL氧化性和内皮血管功能一起进行评估，以解决氧化应激在糖尿病中增强的假设，这是在微血管或大血管疾病的发病之前。 将在伴和不伴视网膜病变的1型糖尿病患者、伴和不伴大血管疾病的2型糖尿病患者、非糖尿病起源的外周血管疾病患者和适当对照中测量F2-异前列腺素的尿排泄。 因为异前列腺素是由花生四烯酸与磷脂酯化原位形成的，我们将分离LDL以测量LDL磷脂含有8-epi-PGF 2a和IPF 2a-I的程度。 我们还将评估LDL对氧化的敏感性和铜诱导氧化过程中LDL中F2-异前列烷形成的时间过程。 肱动脉的内皮依赖性和内皮非依赖性扩张将通过高分辨率、非侵入性血管抗氧化剂维生素E+C测量，维生素E+C将抑制F2-异前列腺素的尿排泄，同时调节LDL对氧化的敏感性和恢复内皮血管功能。 这项研究的结果可能支持的假设，增加氧化应激糖尿病血管并发症的发病之前，并可能表明抗氧化剂在补充其他治疗方法，以预防或改善糖尿病并发症的治疗作用。