Background The cause of accelerated atherosclerosis in rheumatoid arthritis (RA) is still unclear and appears to be multifactorial . Besides the traditional risk factors, also RA-specific risk factors may play a role. Notably, vascular inflammation in the vascular adventitia may be a crucial factor. Elucidating the pathomechanism of cardiovascular (CV) disease in RA is essential in order to provide optimal CV prevention and treatment. Examination of vascular specimens may provide important clues for such an endeavor.
Objectives To compare the gene expression profile in the aortic adventitia in coronary artery disease (CAD) patients with and without RA.
Methods Total RNA was isolated from biopsies of the adventitia of the ascending aorta removed during coronary artery bypass grafting in patients with (n=8) and without (n=8) RA. The gene expression profile was determined using Affymetrix microarray. The CEL files were imported into the Partek Genomics Suite software, and differentially expressed genes were identified by one-way ANOVA (p<0.05; FC>1.1).
Results Non-supervised hierarchical clustering analyses showed that the gene expression profiles clustered into two groups. A total of 15586 transcripts were identified, of which 201 were differentially expressed between the groups (p<0.05). Upstream analysis demonstrated activation of the stress-induced transcriptional regulator NUPR1 in RA patients (z-score: 3.0). Nine target molecules of NUPR1 were identified, including the endothelial dysfunction-related GADD45A , which was up-regulated in RA patients (p=0.006; FC=1.474) (Figure 1).
Conclusions NUPR1 is a known key player in the cellular stress response . Our results indicate that the increased CV risk in RA might be related to activation of NUPR1, with downstream activation of GADD45A, which in turn promotes endothelial dysfunction. Interestingly, NUPR1 has also been linked to heart failure . In theory, NUPR1 might be a target for novel therapy.
Hollan I, Meroni PL, Ahearn JM, Cohen Tervaert JW, Curran S, Goodyear CS, Hestad KA, Kahaleh B, Riggio M, Shields K, Wasko MC: Cardiovascular disease in autoimmune rheumatic diseases. Autoimmunity reviews 2013, 12:1004-1015.
Thum T, Borlak J: LOX-1 receptor blockade abrogates oxLDL-induced oxidative DNA damage and prevents activation of the transcriptional repressor Oct-1 in human coronary arterial endothelium. The Journal of biological chemistry 2008, 283:19456-19464.
Goruppi S, Iovanna JL: Stress-inducible protein p8 is involved in several physiological and pathological processes. The Journal of biological chemistry 2010, 285:1577-1581.
Goruppi S, Patten RD, Force T, Kyriakis JM: Helix-loop-helix protein p8, a transcriptional regulator required for cardiomyocyte hypertrophy and cardiac fibroblast matrix metalloprotease induction. Molecular and cellular biology 2007, 27:993-1006.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.