Differential expression of vitamin D associated genes in the aorta of coronary artery disease patients with and without rheumatoid arthritis

Abstract

BackgroundVitamin D has an important role in the immune system, and has been linked to rheumatoid arthritis (RA) and coronary artery disease (CAD). The exact mechanisms by which vitamin D is involved in these processes are still unclear. Therefore, we wanted to search for differences in expression of genes involved in the vitamin D receptor (VDR) activation pathway and genes that are known to alter upon vitamin D stimulation, in the aortic adventitia of CAD patients with and without RA.MethodsAffymetrix microarray was used to determine gene expression profile in surgical specimens from the adventitia of the ascending aorta of CAD patients with RA (n = 8) and without RA (n = 8) from the Feiring Heart Biopsy Study.ResultsWe identified three vitamin D associated genes that were differentially expressed between RA and non-RA patients: Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (FC = 1.47; p = 0.006), Nuclear Receptor Co-repressor 1 (NCOR1) (FC = 1,21; p = 0.005) and paraoxonases 2 (PON2) (FC = -1.37; p = 0.01). High expression of GADD45A in RA tissues was confirmed by real-time qRT-PCR. GADD45A expression correlated with plasma levels of 1,25(OH)2D3 (rs = 0.69; p = 0.003).ConclusionsMicroarray analyses revealed higher expression of GADD45A and NCOR1; and lower expression of PON2 in the aortic adventitia of RA than non-RA patients. Further studies are needed to elucidate if and how GADD45A, NCOR1 and PON2 are involved in the development of accelerated atherosclerosis in RA. In theory, some of these factors might have proatherogenic effects whereas others might reflect an underlying vascular pathology promoting atherogenesis (such as vascular stress).

The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification

“…Additionally, the vitamin D associated gene expression within aortic tissue might be influenced in patients with rheumatoid arthritis. Paraoxonases 2, which had antioxidative properties during atherosclerotic processes, was regulated by vitamin D. The expression was lessened during the inflammation [139]. Vitamin D was associated with lessening the inflammatory cytokine.…”

GADD45A: With or without you

“…Although Gadd45a gene expression was not modified in peripheral blood mononuclear cells of these RA patients, 20 another study has reported a higher expression of Gadd45a in the adventitia of the ascending aorta of patients with RA compared to non-RA patients (Table 1). 161 In patients with psoriasis, Gadd45a is expressed at higher levels in peripheral and in dermal infiltrating T cells, although no differences are found regarding p38 MAPK activity. 157 The same authors reported that the GADD45A target Uchl1 (ubiquitin carboxyl terminal esterase L1) was hypermethylated at its promoter in psoriatic skin, and that…”

“…Although Gadd45a gene expression was not modified in peripheral blood mononuclear cells of these RA patients, 20 another study has reported a higher expression of Gadd45a in the adventitia of the ascending aorta of patients with RA compared to non‐RA patients (Table 1). 161 …”

Vitamin D as A Protector of Arterial Health: Potential Role in Peripheral Arterial Disease Formation

“…Studies shows that the primary activation step after 1α,25(OH) 2 D 3 -VDR complex is the transient opening or closing of the chromatin at specific enhancer and TSS with RNA polymerase II and other nuclear adaptor proteins, which determines the regulation (activation or suppression) of primary vitamin D target genes [145] (Figure 4). Nuclear Receptor Corepressor 1 (NCOR1) is a co-repressor that contains nuclear receptor interacting domains and interacts with various nuclear receptors, including VDR [146]. NCOR1 recruits histone deacetylase enzymes (HDACs) which deacetylase histone-tails and thereby condense the DNA structure and prevent gene-transcription.…”