Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.
Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.
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DOI：
10.1016/j.cellimm.2012.03.007
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发表时间：
2012-03
影响因子：
4.3
通讯作者：
Hammad, Samar M.
中科院分区：
文献类型：
--
作者：
Al Gadban, Mohammed M.;German, Jashalynn;Truman, Jean-Philip;Soodavar, Farzan;Riemer, Ellen C.;Twal, Waleed O.;Smith, Kent J.;Heller, Demarcus;Hofbauer, Ann F.;Oates, Jim C.;Hammad, Samar M.
系统性红斑狼疮（SLE）患者显示正常血管舒张所需的内皮型一氧化氮合酶（eNOS）功能受损。SLE患者表达诱导型一氧化氮合酶（iNOS）的代偿活性增加，产生过量的一氧化氮，可能导致炎症。我们研究了分别编码iNOS和eNOS的NOS 2和NOS 3基因缺失对MRL/lpr狼疮小鼠模型中加速血管疾病的影响。与对应的MRL/lpr对照组相比，NOS 2和NOS 3敲除（KO）MRL/lpr小鼠的甘油三酯（分别为23%和35%）、神经酰胺（分别为45%和21%）和1-磷酸鞘氨醇（S1 P）（21%）血浆水平较高。NOS 2和NOS 3 KO MRL/lpr小鼠中抗炎细胞因子白细胞介素10（IL-10）的血浆水平低于对应对照组（分别为53%和80%）。在来自NOS 2和NOS 3 KO MRL/lpr小鼠的动脉瘤中检测到外膜中的结节样病变。病变的免疫组织化学评价显示活化的内皮细胞和载脂巨噬细胞（泡沫细胞），鞘氨醇激酶1表达升高，氧化低密度脂蛋白免疫复合物（oxLDL-IC）。研究结果表明，在NOS 2和NOS 3 KO MRL/lpr小鼠中，晚期血管疾病可能是由血浆甘油三酯、神经酰胺和S1 P升高;血浆IL-10降低;以及oxLDL-IC在血管壁中积聚介导的。结果揭示了可能的新靶点，以减轻狼疮相关并发症。
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.
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影响因子：
5.7
作者：
Brack, A;Geisler, A;Weyand, CM
通讯作者：
Weyand, CM
影响因子：
3.6
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Florio, T;Arena, S;Schettini, G
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9.1
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Posadas-Romero, Carlos
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4.8
作者：
Bulotta, S;Barsacchi, R;Clementi, E
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Clementi, E