Nitric Oxide Metabolism in Statin-treated Pediatric SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）以动脉粥样硬化加速为特征。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以一氧化氮（NO）和诱导型一氧化氮合酶（NOS2）表达增加为特征。相反，内皮功能障碍的特征是由于NOS内皮异构体（NOS3）活性降低而导致动脉血管舒张功能减弱。在动物模型中，NOS2缺乏的动物动脉粥样硬化的发展减弱，而NOS3缺乏的动物动脉粥样硬化的发展加速。我们认为，SLE患者内皮细胞和巨噬细胞NOS2过表达可导致动脉粥样硬化加速，而NOS2过表达可抑制内皮细胞NOS3活性，诱导内皮功能障碍。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，包括降低全身NO代谢物水平和NOS2表达。相反，他汀类药物治疗内皮功能的改善与nos3介导的NO生成的增加有关。由于NOS2比NOS3产生更多的NO，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表达的降低有关。先前的研究表明NOS2和NOS3多态性与全身NO代谢物水平和血管疾病有关。因此，我们认为NOS2和NOS3多态性与SLE患者动脉粥样硬化加速有关。作为儿童红斑狼疮动脉粥样硬化预防（APPLE）研究的一部分，对SLE疾病活动性的仔细临床测量和动脉粥样硬化进展的放射学测量将为了解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一个极好的机会。APPLE试验是美国国立卫生研究院资助的一项研究，旨在确定280例儿童SLE患者接受他汀类药物治疗对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代谢测量外，该应用程序的优势之一是我们建议收集小儿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，并进行对种群亚结构具有鲁棒性的遗传关联测试。此外，这些DNA样本将构成未来小儿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.