Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms222111419
Keywords
high-density lipoprotein (HDL); electronegative subfractions of HDL; H5; liquid chromatography/mass spectrometry (LC/MS); lipoprotein a (Lp(a)); atherosclerosis; rheumatoid arthritis (RA)
Funding
- China Medical University Hospital [DMR-110-196]
- Ministry of Science and Technology, Taiwan [MOST 110-2314-B-039-051]
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The study found that the most electronegative subfraction of HDL-c (H5%) was higher in patients with rheumatoid arthritis compared to healthy controls, and H5% was a significant predictor for subclinical atherosclerosis in RA. Additionally, H5 induced higher levels of proinflammatory cytokines in cells and promoted foam cell formation, suggesting its involvement in RA-related atherosclerosis.
Although the heterogeneity of high-density lipoprotein-cholesterol (HDL-c) composition is associated with atherosclerotic cardiovascular risk, the link between electronegative subfractions of HDL-c and atherosclerosis in rheumatoid arthritis (RA) remains unknown. We examined the association of the percentage of the most electronegative subfraction of HDL-c (H5%) and RA-related atherosclerosis. Using anion-exchange purification/fast-protein liquid chromatography, we demonstrated significantly higher H5% in patients (median, 7.2%) than HC (2.8%, p < 0.005). Multivariable regression analysis revealed H5% as a significant predictor for subclinical atherosclerosis. We subsequently explored atherogenic role of H5 using cell-based assay. The results showed significantly higher levels of IL-1 beta and IL-8 mRNA in H5-treated (mean & PLUSMN; SD, 4.45 & PLUSMN; 1.22 folds, 6.02 & PLUSMN; 1.43-folds, respectively) than H1-treated monocytes (0.89 & PLUSMN; 0.18-folds, 1.03 & PLUSMN; 0.26-folds, respectively, both p < 0.001). In macrophages, H5 upregulated the mRNA and protein expression of IL-1 beta and IL-8 in a dose-dependent manner, and their expression levels were significantly higher than H1-treated macrophages (all p < 0.001). H5 induced more foam cell formation compared with H1-treated macrophages (p < 0.005). In addition, H5 has significantly lower cholesterol efflux capacity than H1 (p < 0.005). The results of nanoLC-MS/MS approach reveal that the best discriminator between high-H5% and normal-H5% is Apo(a), the main constituent of Lp(a). Moreover, Lp(a) level is a significant predictor for high-H5%. These observations suggest that H5 is involved in RA-related atherosclerosis.
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