Background/Purpose:

Premature atherosclerosis is widely recognized as a significant co-morbid condition of systemic lupus erythematosus (SLE), but exact mechanisms are unknown.  Although traditional cardiovascular risk factors correlate with subclinical atherosclerosis in cohort studies, they are unable to fully account for the increased risk.  Longer SLE duration correlates with higher risk for cross-sectional and longitudinal progression of atherosclerosis, suggesting that chronic inflammation and/or oxidative stress could be SLE-specific factors contributing to accelerated atherosclerosis.  Plasma pro-oxidant, pro-inflammatory HDL (piHDL) is also closely linked to presence and progression of plaque in SLE and can abnormally activate monocytes, the major immune cell type involved in atherosclerosis.  Recent data have linked oxidative stress to epigenetic aberrations in non-autoimmune subjects with atherosclerosis, and we wanted to examine whether these mechanisms could partially explain the risk of premature atherosclerosis in SLE. 

Methods:

Patients were recruited from a pre-existing cohort to study atherosclerosis in SLE.  Carotid ultrasound was performed to determine the presence or absence of subclinical atherosclerosis (plaque).  HDL status was determined by a fluorometric assay examining oxidation of human LDL in the presence of patient HDL.  RNA was isolated from freshly isolated primary monocytes from 51 SLE patients subdivided into three groups: a) plaque+piHDL+ (LPP, n=15), b) plaque-piHDL+ (LPN, n=18), and c) plaque-piHDL- (LNN, n=18).  Whole-genome monocyte expression analysis was performed using Affymetrix Human U133+2.0 chips.  dChip software (Li lab, Harvard) was utilized to determine differentially expressed transcripts between the three groups.  Clustering was performed and graphed using Cluster and TreeView (Eisen lab, UC Berkeley).  Confirmation of significantly altered transcript levels was determined using quantitative PCR.

Results:

Expression of 385 genes was significantly altered between the LPP and LNN groups (fold change ≥1.2 or ≤-1.2, p≤0.05, false discovery rate 6.8%).  The majority of the differentially-expressed genes were downregulated in LPP (vs. LNN).  A large proportion of genes were involved in histone acetylation, DNA methylation, and oxidative stress (14% of the total; <5% expected).  Multiple methyltransferases (MT) were downregulated in LPP subjects, including DNMT1.  The presence of piHDL correlates with lower MT, acetyltransferase, and oxidative stress transcripts, as many of the same transcripts were downregulated in the LPN group (vs. LNN).  Conversely, the antioxidants peroxiredoxin2 (PRDX2) and superoxide dismutase 2 (SOD2) were upregulated in LPN and LPP groups versus LNN.  Unsupervised clustering placed almost all samples into their piHDL/plaque subgroups.

Conclusion:

The presence of piHDL correlates with dysregulation of multiple epigenetic and oxidative stress-related transcripts in circulating monocytes of SLE patients.  Further epigenetic and biochemical experiments will determine the role of lipid and protein oxidation in the initiation of premature atherosclerosis in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pro-inflammatory-hdl-and-subclinical-atherosclerosis-are-associated-with-altered-expression-of-epigenetic-and-oxidative-stress-related-gene-transcripts-in-sle/