title: Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.
abstract: 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.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al Gadban
authors.forename: Jashalynn
authors.initials: J
authors.lastname: German
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Truman
authors.forename: Farzan
authors.initials: F
authors.lastname: Soodavar
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Riemer
authors.forename: Waleed O
authors.initials: WO
authors.lastname: Twal
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Demarcus
authors.initials: D
authors.lastname: Heller
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hofbauer
authors.forename: Jim C
authors.initials: JC
authors.lastname: Oates
authors.forename: Samar M
authors.initials: SM
authors.lastname: Hammad
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000378:metabolism*; D013107:Sphingolipids / Q000097:blood*
chemical_list: D008077:Lipoproteins, LDL; D013107:Sphingolipids; C099252:oxidized low density lipoprotein; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse