Nitric Oxide Metabolism in Statin-treated Pediatric SLE

描述(申请人提供)：系统性红斑狼疮(SLE)的特征是动脉粥样硬化加速。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。系统性红斑狼疮患者动脉粥样硬化病变和血管内皮细胞的特点是一氧化氮(NO)和诱导型一氧化氮合酶(NOS2)的表达增加。相反，内皮功能障碍的特征是由于内皮型一氧化氮合酶(NOS3)活性降低而导致的动脉血管扩张减弱。在动物模型中，动脉粥样硬化的发展在NOS2缺乏的动物中减少，在NOS3缺乏的动物中加速。我们认为SLE患者内皮和巨噬细胞NOS2的过度表达导致动脉粥样硬化的加速，NOS2的过度表达可能抑制内皮NOS3的活性，导致内皮功能障碍。他汀类药物治疗可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的表达。相反，他汀类药物对内皮功能的改善与NOS3介导的NO产生的增加有关。由于NOS2在数量上比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和巨噬细胞NOS2表达的减少有关。以往的研究表明，NOS2和NOS3基因多态性与全身NO代谢产物水平和血管疾病有关。因此，我们认为NOS2和NOS3基因多态性与SLE动脉粥样硬化的加速有关。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对动脉粥样硬化进展的放射测量，为了解SLE患者一氧化氮代谢测量、动脉粥样硬化进展和他汀类药物治疗之间的关系提供了一个极好的机会。APPLE试验是由美国国立卫生研究院资助的一项研究，它将确定他汀类药物前瞻性治疗280名儿童SLE患者对动脉粥样硬化进展的影响。除了我们建议的在Apple试验参与者中进行NO代谢的措施外，这项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，并进行对种群亚结构稳健的遗传关联测试。此外，这些DNA样本将成为未来儿童系统性红斑狼疮基因分析的重要来源。

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.