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. ? ? ?
