Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.

Systemic lupus erythematosus (SLE) patients display impaired endothelial nitric oxide synthase (eNOS) function required for normal vasodilatation. SLE patients express increased compensatory activity of inducible nitric oxide synthase (iNOS) generating excess nitric oxide that may result in inflammation. We examined the effects of genetic deletion of NOS2 and NOS3, encoding iNOS and eNOS respectively, on accelerated vascular disease in MRL/lpr lupus mouse model. NOS2 and NOS3 knockout (KO) MRL/lpr mice had higher plasma levels of triglycerides (23% and 35%, respectively), ceramide (45% and 21%, respectively), and sphingosine 1-phosphate (S1P) (21%) compared to counterpart MRL/lpr controls. Plasma levels of the anti-inflammatory cytokine interleukin 10 (IL-10) in NOS2 and NOS3 KO MRL/lpr mice were lower (53% and 80%, respectively) than counterpart controls. Nodule-like lesions in the adventitia were detected in aortas from both NOS2 and NOS3 KO MRL/lpr mice. Immunohistochemical evaluation of the lesions revealed activated endothelial cells and lipid-laden macrophages (foam cells), elevated sphingosine kinase 1 expression, and oxidized low-density lipoprotein immune complexes (oxLDL-IC). The findings suggest that advanced vascular disease in NOS2 and NOS3 KO MRL/lpr mice maybe mediated by increased plasma triglycerides, ceramide and S1P; decreased plasma IL-10; and accumulation of oxLDL-IC in the vessel wall. The results expose possible new targets to mitigate lupus-associated complications.

系统性红斑狼疮（SLE）患者表现出正常血管舒张所需的内皮型一氧化氮合酶（eNOS）功能受损。SLE患者诱导型一氧化氮合酶（iNOS）的代偿性活性增加，产生过量的一氧化氮，这可能导致炎症。我们研究了分别编码iNOS和eNOS的NOS2和NOS3基因缺失对MRL/lpr狼疮小鼠模型中加速性血管疾病的影响。与相应的MRL/lpr对照小鼠相比，NOS2和NOS3基因敲除（KO）的MRL/lpr小鼠血浆中甘油三酯（分别为23%和35%）、神经酰胺（分别为45%和21%）以及1 - 磷酸鞘氨醇（S1P）（21%）水平更高。NOS2和NOS3基因敲除的MRL/lpr小鼠血浆中抗炎细胞因子白细胞介素 - 10（IL - 10）水平（分别为53%和80%）低于相应对照小鼠。在NOS2和NOS3基因敲除的MRL/lpr小鼠的主动脉外膜中均检测到结节样病变。对病变的免疫组织化学评估显示内皮细胞活化、富含脂质的巨噬细胞（泡沫细胞）、鞘氨醇激酶1表达升高以及氧化型低密度脂蛋白免疫复合物（oxLDL - IC）。研究结果表明，NOS2和NOS3基因敲除的MRL/lpr小鼠的晚期血管疾病可能是由血浆甘油三酯、神经酰胺和S1P增加、血浆IL - 10降低以及血管壁中oxLDL - IC的积聚所介导。这些结果揭示了可能减轻狼疮相关并发症的新靶点。