NITRIC OXIDE INHIBITION OF APO-B-MEDIATED LDL OXIDATION

在这个新的FIRCA应用程序中描述的实验目标解决了西方国家发病率和死亡率的主要来源动脉粥样硬化的基本机制。它们还为进一步扩大阿拉巴马大学伯明翰医学院和乌拉圭蒙得维的亚共和国大学医学院的研究人员在自由基生物学和医学方面共同开展的互利合作研究和培训活动奠定了基础。具体来说，母体资助的主题，即- no介导膜脂和脂蛋白的抗氧化作用，将通过解决- no可以通过与蛋白质基自由基相互作用来发挥这些作用的新概念，在一个新的和重要的方向上扩展。我们推测- no在调节LDL氧化过程中起关键作用，其途径是：a)易于扩散到LDL颗粒的表面和核心，从而代表LDL亲脂核心的主要抗氧化物质；b)扩散控制与载脂蛋白-100中心的氨基酸自由基的反应，从而抑制脂质和蛋白质氧化反应。此外，我们假设血管扩张剂-NO与血浆LDL的氨基酸组分apoB-100的化学相互作用有助于浓缩和随后释放-NO，从而减轻氧化LDL的促动脉粥样硬化作用。为了解决这些概念，将追求两个关键的实验目标。我们将1)测量-NO在人血浆LDL中的扩散和分配速率；2)鉴定-NO加合物与载脂蛋白B-100氨基酸自由基，并确定这些新物种的抗氧化和信号作用。这些拟议的研究将为理解no对LDL氧化和随后的动脉粥样硬化事件的开始、传播和解决产生深远影响的机制提供坚实的基础。因此，该研究计划将探索- no与脂蛋白的新型化学相互作用，为- no依赖的抗动脉粥样硬化过程提供新的见解。

The experimental goals described in this new FIRCA application address fundamental mechanisms underlying the principal source of morbidity and mortality in Westernized countries, atherosclerosis. They also serve as the foundation for further expanding the mutually beneficial collaborative research and training activities in free radical biology and medicine shared by investigators at the University of Alabama at Birmingham School of Medicine and the Facultad de Medicina of the Universidad de la Repdblica in Montevideo, Uruguay. Specifically, the theme of the parent grant, that -NO mediates antioxidant actions in membrane lipids and lipoproteins, will be expanded in a new and important direction by addressing the novel concept that -NO can exert these effects by interacting with protein- based radicals. It is hypothesized that -NO plays a critical role in modulating LDL oxidation by: a) a facile diffusion capacity into both the surface and the core of the LDL particle, thus representing the major antioxidant species in the lipophilic core of LDL, and b) diffusion- controlled reactions with apoB-100-centered amino acid radicals, thus inhibiting both lipid and protein oxidation reactions. In addition, we postulate that chemical interactions of the vasodilator -NO with amino acid components of plasma LDL apoB-100 serve to concentrate and later release -NO, thus mitigating the otherwise pro-atherogenic effects of oxidized LDL. To address these concepts, two key experimental aims will be pursued. We will 1) Measure rates of -NO diffusion and partitioning into human plasma LDL and 2) Identify -NO adducts with apo B-100 amino acid radicals and define the antioxidant and signaling roles of these novel species. These proposed investigations will provide a strong foundation for understanding mechanisms underlying the profound impact that -NO has on the initiation, propagation and resolution of both LDL oxidation and consequent atherogenic events. Thus, the research plan will explore novel chemical interactions of -NO with lipoproteins, yielding new insight into -NO-dependent anti- atherogenic processes.