Native LDL, Cholesterol and Impaired Vasodilation

描述(由申请人提供)：最近的报告表明，抑制血管功能障碍的一种方法是改变血浆脂蛋白的载脂蛋白特性。用载脂蛋白A-1模拟物“4F”治疗胆固醇喂养的低密度脂蛋白受体(-/-)小鼠，显著减少病变形成(&gt；75%)，而不显著改变血浆胆固醇水平。因此，这种竞争性更新应用的两个主要目标是确定低密度脂蛋白(LDL)受损的机制以及4F在高胆固醇血症期间保护血管扩张的机制。本实验室最近的报告表明，天然低密度脂蛋白和最低限度修饰低密度脂蛋白对内皮超氧阴离子(02-)的生成有不同的调节作用。天然低密度脂蛋白解偶联内皮型一氧化氮合酶(ENOS)活性，mm-低密度脂蛋白解偶联内皮型一氧化氮合酶(ENOS)，激活黄嘌呤氧化酶和NAD(P)H氧化还原酶，增加内皮细胞02的生成。初步结果表明，低密度脂蛋白对内皮细胞02生成的许多影响可以被载脂蛋白A-1模拟物4F逆转，它有效地将低密度脂蛋白转变为非致动脉粥样硬化的脂蛋白。喂食高脂胆固醇西方饮食的LDLR(-/-)小鼠表现出对乙酰胆碱的血管扩张功能受损，而4F处理的LDLR(-/-)小鼠的微血管反应与对照反应基本相同。这些数据表明，4F使一氧化氮(NO)和02-的平衡重新朝向NO，以恢复血管扩张。细胞生物学研究表明，虽然低密度脂蛋白和低密度脂蛋白减少了HSP90与eNOS的相互作用以促进解偶联酶的活性，但在低密度脂蛋白中加入4F可以恢复HSP90与eNOS的联系，增加似乎是偶联酶的活性。在载脂蛋白A-1类似物增加血浆脂蛋白类HDL功能的基础上，我们的数据表明，高密度脂蛋白在减少内皮02“的产生方面起着关键作用，高密度脂蛋白被认为是在高胆固醇血症时损害血管扩张的。研究4F如何保护血管功能将提供对低密度脂蛋白损害血管扩张和高密度脂蛋白保护血管功能的机制的新理解。

DESCRIPTION (provided by applicant): Recent reports suggest that one way to inhibit vascular dysfunction is to change the apolipoprotein character of plasma lipoproteins. Treating cholesterol-fed LDLr(-/-) mice with an apolipoprotein A-1 mimetic, "4F," significantly reduces lesion formation (>75%) without significant changes in plasma cholesterol levels. Accordingly, the two major goals of this competitive renewal application are to determine the mechanisms by which low-density lipoprotein (LDL) impair and by which 4F preserves vasodilation during hypercholesterolemia. Recent reports from this laboratory demonstrate that native LDL and minimally modified (mm) LDL differentially regulate endothelial superoxide anion (02-) generation. Native LDL uncouples endothelial nitric oxide synthase (eNOS) activity while mm-LDL uncouples eNOS, activates xanthine oxidase and NAD(P)H oxidoreductase to increase endothelial 02- generation. Preliminary results indicate that many of the effects of LDL on endothelial 02- generation can be reversed by the apolipoprotein A-1 mimetic, 4F, which effectively turns LDL into a non-atherogenic lipoprotein. LDLr(-/-) mice fed high fat cholesterol western diets demonstrate impaired vasodilation to acetylcholine, where as vascular responses of microvessels from LDLr(-/-) mice treated with 4F are essential the same as control responses. These data suggest that 4F shifts the balance of nitric oxide (NO) and 02- back toward .NO to restore vasodilation. Cell biology studies have shown that although LDL and mm-LDL decrease hsp90 interactions with eNOS to promote uncoupled enzyme activity, adding 4F to LDL incubations restores hsp90 association with eNOS, increasing what appears to be coupled enzyme activity. On the basis that apo A-1 mimetics increase HDLlike function of plasma lipoproteins, our data suggest that HDL plays a critical role in decreasing endothelial 02"- generation, which is hypothesized to impair vasodilation during hypercholesterolemia. Investigations in to how 4F protects vascular function will provide new understanding of the mechanisms by which LDL impairs vasodilation and HDL protects vascular function.