Nitric Oxide Metabolism in Statin-treated Pediatric SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）的特征是加速动脉粥样硬化。巨噬细胞介导的血管炎症和内皮功能障碍在动脉粥样硬化的发病机制中起重要作用。SLE患者的动脉粥样硬化病变和内皮的特征在于一氧化氮（NO）和诱导型一氧化氮合酶（NOS 2）的表达增加。相比之下，内皮功能障碍的特征在于由于NOS（NOS3）的内皮同种型的活性降低而导致的动脉血管舒张减少。在动物模型中，动脉粥样硬化的发展在NOS2缺陷动物中减少，在NOS3缺陷动物中加速。我们认为，内皮细胞和巨噬细胞NOS 2的过度表达导致SLE患者动脉粥样硬化的加速，而NOS 2的过度表达可能抑制内皮细胞NOS 3的活性，导致内皮功能障碍。他汀类药物治疗减缓动脉粥样硬化的进展，并与炎症的减少有关，包括NO代谢物和NOS2表达的全身水平的降低。相比之下，他汀类药物治疗对内皮功能的改善与NOS3介导的NO产生的增加有关。由于NOS2产生的NO量大于NOS3，我们认为他汀类药物治疗SLE患者将与全身NO代谢物水平的降低以及内皮细胞和巨噬细胞NOS2表达的降低相关。以往的研究表明NOS2和NOS3多态性与全身NO代谢物水平和血管疾病相关。因此，我们认为NOS2和NOS3多态性与SLE动脉粥样硬化加速相关。作为儿科红斑狼疮动脉粥样硬化预防（APPLE）研究的一部分，对SLE疾病活动性进行仔细的临床测量和对动脉粥样硬化进展进行放射学测量，为了解SLE患者NO代谢测量、动脉粥样硬化进展和他汀类药物治疗之间的关系提供了极好的机会。APPLE试验是NIH资助的一项研究，旨在确定他汀类药物治疗对280例儿童SLE患者动脉粥样硬化进展的影响。除了我们提出的APPLE试验参与者NO代谢的措施外，该应用的优势之一是我们建议收集儿童SLE患者父母的遗传信息。这些信息将使我们能够更精确地估计单倍型关系，并进行对群体亚结构具有鲁棒性的遗传关联测试。此外，这些DNA样本将构成未来儿童SLE遗传分析的重要资源。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by accelerated atherosclerosis. Macrophage-mediated vascular inflammation and endothelial dysfunction play important roles in the pathogenesis of atherosclerosis. Atherosclerotic lesions and the endothelium of SLE patients are characterized by increased expression of nitric oxide (NO) and the inducible isoform of nitric oxide synthase (NOS2). In contrast, endothelial dysfunction is characterized by diminished arterial vasodilation due to decreases in the activity of the endothelial isoform of NOS (NOS3). In animal models, the development of atherosclerosis is diminished in NOS2 deficient animals and is accelerated in NOS3 deficient animals. We believe that overexpression of endothelial and macrophage NOS2 in SLE patients leads to accelerated atherosclerosis, and over-expression of NOS2 may inhibit endothelial NOS3 activity and induce endothelial dysfunction. Statin therapy slows the progression of atherosclerosis and is associated with reductions in inflammation, including reductions in systemic levels of NO metabolites and NOS2 expression. In contrast, improvements in endothelial function with statin therapy are associated with increases in NOS3-mediated NO production. Because NOS2 produces quantitatively greater amounts of NO than NOS3, we believe that statin therapy in SLE patients will be associated with reductions in systemic NO metabolite levels and with reductions in endothelial and macrophage NOS2 expression. Previous studies indicated an association of NOS2 and NOS3 polymorphisms with systemic NO metabolite levels and vascular disease. Therefore, we believe that NOS2 and NOS3 polymorphisms are associated with accelerated atherosclerosis in SLE. The careful clinical measures of SLE disease activity and radiologic measures of atherosclerosis progression that will be performed as part of the Atherosclerotic Prevention in Pediatric Lupus Erythematosus (APPLE) study, provide an excellent opportunity to understand the relationship between measures of NO metabolism, progression of atherosclerosis and statin therapy in SLE patients. The APPLE trial is an NIH funded study that will determine the effect of prospectively treating 280 pediatric SLE patients with statin therapy on the progression of atherosclerosis. In addition to our proposed measures of NO metabolism in APPLE trial participants, one of the strengths of this application is our proposal to collect genetic information on the parents of pediatric SLE patients. This information will allow us to estimate haplotype relationships with greater precision and conduct genetic association tests that are robust to population substructure. In addition, these DNA samples will constitute an important resource for future genetic analyses of pediatric SLE.