Abstract
Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune, systemic, inflammatory disorder predominantly affecting women
The median (IQR) age was 53 (46, 58) and 43 (28, 55) years respectively Compared to healthy control myeloid angiogenic cells (MACs), we observed an impaired capacity of systemic lupus erythematosus (SLE) MACs to generate colonies in terms of both number
Endothelial repair is a recently recognised phenomenon in which damaged vasculature is restored by circulating populations of cells including MACs
Summary
Systemic lupus erythematosus (SLE) is an autoimmune, systemic, inflammatory disorder predominantly affecting women. Patients with SLE have a significantly increased risk of cardiovascular disease which is not explained by traditional risk factors[1]. Endothelial dysfunction and the loss of endothelial integrity precede the development of atherosclerosis[2] and endothelial dysfunction, assessed by flow-mediated dilatation (FMD), is an established risk factor for future cardiovascular events in the general population[3]. Activated IFNα pathways are associated with both active disease and endothelial dysfunction in SLE patients[9], supporting the use of IFNα treatment of MACs as a useful model of SLE. Epidemiological studies show that vitamin D deficiency is associated with future cardiovascular events in the general population[10] and correlates with the presence of endothelial dysfunction[11] and carotid intima-medial thickness[12]. High dose cholecalficerol supplementation has been shown to improve endothelial function over a short time course in some populations[18,19,20,21], the mechanism underpinning the improvements in endothelial function by vitamin D in SLE is unknown
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