Vitamin D Deficiency Is Associated With Endothelial Dysfunction and Increases Type-1 Interferon Gene Expression in a Murine Model of Systemic Lupus Erythematosus

John A. Reynolds, Avi Z. Rosenberg, Carolyne K. Smith, Jamie C. Sergeant, Gillian I. Rice, Tracy A. Briggs, Ian N. Bruce, Mariana J. Kaplan

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Abstract

Objective
Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD) and impaired endothelial repair. Although vitamin D deficiency is associated with increased CVD risk in the general population, a causal relationship has not been demonstrated. We aimed to determine whether vitamin D deficiency directly modulates endothelial dysfunction and immune responses in a murine model of SLE.Methods
Vitamin D deficiency was induced in lupus-prone MRL/lpr mice by dietary restriction for 6 weeks. Endothelium-dependent vasorelaxation was quantified using aortic ring myography, and endothelial repair mechanisms were assessed by evaluating the phenotype and function of bone marrow endothelial progenitor cells (EPCs) and with the use of an in vivo Matrigel plug model. Lupus disease activity was determined by evaluating expression of interferon-stimulated genes (ISGs) in splenic tissue, positivity for serum autoantibodies, and renal histology. To validate the findings, expression of ISGs was also measured in whole blood from vitamin D–deficient and vitamin D–sufficient patients with SLE.Results
Vitamin D deficiency resulted in impaired endothelium-dependent vasorelaxation and decreases in neoangiogenesis without a change in the total number of EPCs. There were no differences in anti–double-stranded DNA titers, proteinuria, or glomerulonephritis (activity or chronicity) between vitamin D–deficient or sufficient mice. Vitamin D deficiency was associated with a trend toward increased ISG expression both in mice and in patients with SLE.Conclusion
These findings indicate that vitamin D deficiency is associated with hampered vascular repair and reduced endothelial function, and may modulate type I interferon responses.
Original languageEnglish
Pages (from-to)2929-2935
Number of pages7
JournalArthritis and Rheumatology
Volume68
Issue number12
Early online date28 Nov 2016
DOIs
Publication statusPublished - 1 Dec 2016

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