Molecular Mechanisms of Atherogenesis in Diabetes

男性糖尿病患者和女性糖尿病患者患动脉粥样硬化性血管疾病的风险都大大增加。 虽然动脉粥样硬化的某些危险因素经常出现在糖尿病患者中，但它们不能充分地 与糖尿病相关的动脉粥样硬化的发病率大大增加。一个重要 贡献者可能是高密度脂蛋白（HDL）的改变，它通常可以防止 通过从巨噬细胞泡沫细胞中去除多余的胆固醇来治疗动脉粥样硬化。 体外和体内研究表明，两种ABC转运蛋白ABCA 1和ABCG 1， 从巨噬细胞到HDL或其载脂蛋白的细胞胆固醇和磷脂。因此， 与糖尿病环境相关，可改变HDL并损害其与ABCA 1和ABCG 1相互作用的能力 很可能会强烈影响动脉粥样硬化的形成。 许多可能改变HDL的生化异常包括葡萄糖和游离脂肪酸水平升高， 酸，糖尿病的代谢标志。我们已经表明，多不饱和脂肪酸（PUFA）， 与葡萄糖或其它活性羰基一起产生类似羟基自由基中间体。 使用气相色谱和质谱的组合，我们检测到氧化的模式， 在高血糖的非人灵长类动物的主动脉组织中通过该途径产生的氨基酸。另一 与人类动脉粥样硬化形成有关的途径是髓过氧化物酶，一种由巨噬细胞表达的血红素蛋白 在人体血管损伤中的作用我们最近发现，3-氯酪氨酸的水平，一种蛋白质的特异性标志物， 在从糖尿病患者动脉粥样硬化组织中分离的HDL中，髓过氧化物酶损伤明显升高， 人类此外，我们发现，蛋氨酸氧化和氯化的一个单一的酪氨酸残基， 载脂蛋白A-I是主要的HDL蛋白，它损害了apoA-I通过细胞内的胆固醇清除细胞内胆固醇的能力。 ABCA 1通路。 我们假设HDL的氧化修饰损害巨噬细胞的胆固醇流出， 在糖尿病血管疾病的发病机制中具有核心重要性。因此，本研究将 确定葡萄糖-PUFA和髓过氧化物酶途径是否触发对HDL的损伤， 促进牙菌斑形成。我们将通过以下补充研究来寻找这些途径的证据： (i)培养的人内皮细胞和单核细胞/巨噬细胞，（ii）小鼠模型，和（iii）分离的HDL 来自对照和糖尿病人的血浆和主动脉组织。我们认为有必要了解 动脉壁损伤的分子机制，以开发针对动脉壁损伤的特异性治疗方法。 糖尿病的致命并发症

Both diabetic men and diabetic women are at greatly increased risk for atherosclerotic vascular disease. Although certain risk factors for atherosclerosis are frequently present in diabetics, they cannot adequately account for the greatly increased incidence of atherosclerosis associated with diabetes. One important contributor could be alterations in high-density lipoprotein (HDL), which normally protects against atherosclerosis by removing excess cholesterol from macrophage foam cells. In vitro and in vivo studies demonstrate that two ABC transporters, ABCA1 and ABCG1, promote efflux of cellular cholesterol and phospholipids from macrophages to HDL or its apolipoproteins. Thus, factors associated with the diabetic milieu that modify HDL and impair its ability to interact with ABCA1 and ABCG1 are likely to strongly influence atherogenesis. The many biochemical abnormalities that might modify HDL include elevated levels of glucose and free fatty acids, the metabolic hallmarks of diabetes. We have shown that polyunsaturated fatty acids (PUFAs) in concert with glucose or other reactive carbonyls generate an intermediate that resembles hydroxyl radical. Using a combination of gas chromatography and mass spectrometry, we detected the pattern of oxidized amino acids generated by this pathway in aortic tissue from hyperglycemic nonhuman primates. Another pathway implicated in human atherogenesis is myeloperoxidase, a heme protein expressed by macrophages in human vascular lesions. We recently found that levels of 3-chlorotyrosine, a specific marker for protein damage by myeloperoxidase, are markedly elevated in HDL isolated from atherosclerotic tissue of diabetic humans. Moreover, we showed that methionine oxidation and chlorination of a single tyrosine residue in apolipoprotein A-l, the major HDL protein, impairs the ability of apoA-l to remove cellular cholesterol by the ABCA1 pathway. We hypothesize that oxidative modifications of HDL impair cholesterol efflux from macrophages and are of central importance in the pathogenesis of diabetic vascular disease. Therefore, this research will determine whether the glucose-PUFA and myeloperoxidase pathways pathway trigger damage to HDL and promote plaque development. We will seek evidence for these pathways through complementary studies of (i) cultured human endothelial cells and monocyte/macrophages, (ii) mouse models, and (iii) HDL isolated from plasma and aortic tissue of control and diabetic humans. We believe it will be essential to understand the molecular mechanisms of artery wall damage in order to develop specific therapies against the devastating complications of diabetes.