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).

BackgroundThe cause of premature cardiovascular disease (CVD) in inflammatory rheumatic diseases (IRDs) has not been fully elucidated. As inflammation may play a role, we wanted to compare the occurrence and extent of inflammatory cell infiltrates (ICIs), small vessel vasculitis, and the amount of adipose tissue and collagen in cardiac biopsies taken from patients with coronary artery disease with and without IRDs.MethodsFrom among the Feiring Heart Biopsy Study subjects, we selected patients undergoing coronary artery bypass grafting from whom paraffin-embedded, formalin-fixed specimens from the right atrium were available. The sample comprised 48 patients with IRD and 40 non-IRD patients. Hematoxylin and eosin staining was used to examine the presence and location of ICIs and vasculitis, and Lendrum (Martius yellow, scarlet, and blue) staining was carried out for collagen and adipose tissue.ResultsEpicardial ICIs were found in 27 (56 %) patients with IRD and 24 (60 %) non-IRD patients. There were no significant differences between patients with IRD and non-IRD patients in the amount of cardiac ICIs and adipose tissue, but patients with IRD had more collagen in the myocardium than non-IRD patients. Small vessel vasculitis was not observed in any cardiac specimen. Patients with epicardial ICIs were, on average, 7 years younger than those without.ConclusionsOur results do not support the notion that inflammation in cardiac peri-, epi-, and myocardium plays a more important role in CVD of patients with IRD than non-IRD patients. The increased amount of collagen in the myocardium of patients with IRD suggests differences in extracellular matrix composition and/or mass, which might play a role in cardiac remodeling, and represent targets for novel therapies against heart failure.

BackgroundVitamin D has an important role in the immune system, and has been linked to inflammation, rheumatoid arthritis (RA) and coronary artery disease (CAD)[1, 2]. However, the exact mechanisms how vitamin D is involved in these processes are still unclear.ObjectivesTo compare expression of vitamin D receptor (VDR) associated genes in the aortic adventitia of CAD patients with and without RA.MethodsRNA was isolated, and Affymetrix microarray was used to determine the gene expression profile in specimens from the ascending aorta in 8 patients with CAD and 8 patients with CAD and RA from the Feiring Heart Biopsy Study. Partek Genomics Suite software was used to identify differentially expressed genes by one-way ANOVA (p<0.05; FC>1.1), and differences in expression of VDR associated genes were determined by Ingenuity Pathway Analysis.ResultsAmong the 15586 transcripts that were identified, pathway analysis determined two genes within the VDR signaling pathway, Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (p=0.006; FC=1.474) and Nuclear Receptor Corepressor 1 (NCOR1) (p=0.005; FC=1,210), that where both up-regulated in RA patients.ConclusionsWe found that GADD45A and NCOR1 were upregulated in the aorta of RA patients. GADD45A induces cell cycle arrest, DNA repair and apoptosis in response to various environmental stresses [3], while NCOR1 has an important role as a gene-specific integrator of positive and negative signals that control inflammation [4]. Based on this finding, we hypothesize that the accelerated atherosclerosis in RA might be related to the up-regulation of GADD45A and NCOR1 through the VDR signaling pathway.ReferencesUrruticoechea-Arana A, Martin-Martinez MA, Castaneda S, Piedra CA, Gonzalez-Juanatey C, Llorca J et al. Vitamin D deficiency in chronic inflammatory rheumatic diseases: results of the cardiovascular in rheumatology [CARMA] study. Arthritis Res Ther 2015;17: 211.Norman PE, Powell JT. Vitamin D and cardiovascular disease. Circ Res 2014;114 2: 379–93.Rosemary Siafakas A, Richardson DR. Growth arrest and DNA damage-45 alpha (GADD45alpha). The international journal of biochemistry & cell biology 2009;41 5: 986–9.Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 2010;10 5: 365–76.Disclosure of InterestNone declared