Background/Purpose: In SLE, cardiovascular complications are a significant contributor to morbidity and death. Importantly, there is an increased prevalence of hypertension in SLE patients compared to healthy controls. We have identified a critical role of isolevuglandins (isoLGs) as activators of the immune system in essential hypertension. IsoLGs are peroxidized products of fatty acids that form as a result of reactive oxygen species. These isoLG adducts participate in the activation of T-cells and contributed. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE.

Methods: To determine the presence of isoLG’s in monocytes of human subjects we recruited 11 subjects with SLE and 10 controls subjects. IsoLG adduct accumulation within antigen presenting cells was performed by flow cytometry and mass spectrometry. Superoxide was measured by incubation with dihydroethidium and subsequent high performance liquid chromatography. Flow cytometry was performed with a single chain antibody that recognizes isoLG adducted lysine residues independent of the peptide backbone. CD11c⁺ and CD14⁺ monocytes were analyzed for the presence of isoLG adducts. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks. Animals were sacrificed at 32 weeks of age and C57BL/6 and NZW were used as controls. Blood pressure was analyzed by radiotelemetry. Immune cell accumulation was determined by flow cytometry and the presence of anti-isoLG adduct antibodies was determined by a capture enzyme linked immunosobent assay (ELISA).

Results: By flow cytometry and mass spectrometry we found marked accumulation of isoLG adducts within CD11c⁺ and CD14⁺ antigen presenting cells in SLE subjects compared to control. This was accompanied by an increase in superoxide production in CD14⁺ monocytes. In animals, treatment with 2-HOBA attenuated blood pressure in both mouse models. Immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model of SLE as measured by urinary albumin/creatinine ratio and histologic scoring. Similarly, there is a significant reduction in bone marrow plasma cell accumulation and anti-double stranded DNA (anti-dsDNA) titers in treated animals. Finally we have detected anti-isoLG-adduct IgG in serum collected from both mouse models.

Conclusion: These studies define a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE. Moreover, they suggest a potential therapeutic strategy for the treatment of SLE and associated cardiovascular disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-role-of-lipid-peroxidation-in-systemic-lupus-erythematosus-associated-cardiovascular-disease/