PATHOPHYSIOLOGICAL CONCENTRATIONS OF GLUCOSE PROMOTE OXIDATIVE MODIFICATION OF LOW-DENSITY-LIPOPROTEIN BY A SUPEROXIDE-DEPENDENT PATHWAY
PATHOPHYSIOLOGICAL CONCENTRATIONS OF GLUCOSE PROMOTE OXIDATIVE MODIFICATION OF LOW-DENSITY-LIPOPROTEIN BY A SUPEROXIDE-DEPENDENT PATHWAY
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DOI：
10.1172/jci117396
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发表时间：
1994-08-01
影响因子：
15.9
通讯作者：
CHAIT, A
中科院分区：
文献类型：
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作者：
KAWAMURA, M;HEINECKE, JW;CHAIT, A
氧化型脂蛋白可能在动脉粥样硬化的发病机制中起重要作用。由于糖尿病患者特别容易发生血管疾病，葡萄糖自氧化和蛋白质糖化产生活性氧，我们探讨了葡萄糖在脂蛋白氧化中的作用。在糖尿病状态下观察到的浓度下，葡萄糖可增强低密度脂蛋白（LDL）的氧化。共轭二烯，硫代巴比妥酸反应物质，电泳迁移率，并通过巨噬细胞的降解增加时，低密度脂蛋白在葡萄糖的存在下被修改。相反，游离赖氨酸基团和成纤维细胞降解减少。虽然反应性赖氨酸基团的损失可能是由于氧化修饰或非酶糖化载脂蛋白B-100，抑制脂质过氧化的金属螯合剂，二乙烯三胺五乙酸，阻止游离赖氨酸的变化。因此，赖氨酸残基的糖化不太可能解释在葡萄糖存在下修饰的LDL的巨噬细胞和成纤维细胞摄取的改变。超氧化物歧化酶部分阻断了葡萄糖介导的LDL氧化增强作用，而丁基羟基甲苯几乎完全抑制了葡萄糖介导的LDL氧化增强作用。这些发现表明，葡萄糖通过涉及超氧化物的氧化途径增强LDL脂质过氧化，并且增加了糖尿病的慢性高血糖加速脂蛋白氧化，从而促进糖尿病血管疾病的可能性。
Oxidized lipoproteins may be important in the pathogenesis of atherosclerosis. Because diabetic subjects are particularly prone to vascular disease, and glucose autoxidation and protein glycation generate reactive oxygen species, we explored the role of glucose in lipoprotein oxidation. Glucose enhanced low density lipoprotein (LDL) oxidation at concentrations seen in the diabetic state. Conjugated dienes, thiobarbituric acid reactive substances, electrophoretic mobility, and degradation by macrophages were increased when LDL was modified in the presence of glucose. In contrast, free lysine groups and fibroblast degradation were reduced. Although loss of reactive lysine groups could be due to either oxidative modification or nonenzymatic glycation of apolipoprotein B-100, inhibition of lipid peroxidation by the metal chelator, diethylenetriamine pentaacetic acid, blocked the changes in free lysines. Thus, glycation of lysine residues is unlikely to account for the alterations in macrophage and fibroblast uptake of LDL modified in the presence of glucose. Glucose-mediated enhancement of LDL oxidation was partially blocked by superoxide dismutase and nearly completely inhibited by butylated hydroxytoluene. These findings indicate that glucose enhances LDL lipid peroxidation by an oxidative pathway involving superoxide and raise the possibility that the chronic hyperglycemia of diabetes accelerates lipoprotein oxidation, thereby promoting diabetic vascular disease.