NITRIC OXIDE INHIBITION OF APO-B-MEDIATED LDL OXIDATION

在这个新的FIRCA申请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自由基生物学和医学方面的互利合作研究和培训活动奠定了基础，这些活动由亚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共同开展。具体而言，主题的母基金，即-NO介导的膜脂质和脂蛋白的抗氧化作用，将扩大在一个新的和重要的方向，通过解决新的概念，-NO可以发挥这些作用，通过与蛋白质为基础的自由基相互作用。假设-NO通过以下方式在调节LDL氧化中起关键作用：a）容易扩散到LDL颗粒的表面和核心中的能力，因此代表LDL的亲脂性核心中的主要抗氧化剂种类，和B）与apo B-100中心的氨基酸自由基的扩散控制反应，因此抑制脂质和蛋白质氧化反应.此外，我们假设，化学相互作用的血管扩张剂-NO与血浆LDL载脂蛋白B-100的氨基酸成分的浓度和后来释放-NO，从而减轻了氧化LDL的促动脉粥样硬化的影响。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扩散和分配到人血浆LDL中的速率和2）鉴定-NO与载脂蛋白B-100氨基酸自由基的加合物，并确定这些新物种的抗氧化和信号作用。这些拟议的调查将提供一个强有力的基础，了解机制的深刻影响，-NO的启动，传播和解决LDL氧化和随之而来的动脉粥样硬化事件。因此，该研究计划将探索新的化学相互作用的-NO与脂蛋白，产生新的见解-NO依赖的抗动脉粥样硬化过程。

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.