The Potential Role of Electronegative High-Density Lipoprotein H5 Subfraction in RA-Related Atherosclerosis

• Published in: International Journal of Molecular Sciences Vol. 22; no. 21; p. 11419
• Main Authors: Chang, Ching-Kun, Cheng, Wei-Chung, Ma, Wen-Lung, Chen, Po-Ku, Chen, Chu-Huang, Shen, Pei-Chun, Chen, Chia-Ching, Chang, Shih-Hsin, Lai, Yi-Hua, Chen, Der-Yuan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.10.2021; MDPI
• Subjects: Adult; Arthritis, Rheumatoid; Arthritis, Rheumatoid - pathology; Atherosclerosis; Atherosclerosis - pathology; Biomarkers; Cell Line, Tumor; Chemokines; Cholesterol; Cholesterol, HDL; Cholesterol, HDL - blood; Cholesterol, HDL - chemistry; Chromatography, Liquid; Cytokines; electronegative subfractions of HDL; Female; Foam Cells; Foam Cells - metabolism; H5; High density lipoprotein; high-density lipoprotein (HDL); Humans; Inflammation; Interleukin-1beta; Interleukin-1beta - biosynthesis; Interleukin-1beta - genetics; Interleukin-8; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Lipids; lipoprotein a (Lp(a)); Lipoprotein(a); Lipoprotein(a) - blood; Lipoproteins; liquid chromatography/mass spectrometry (LC/MS); Macrophages; Macrophages - metabolism; Male; Mass Spectrometry; Middle Aged; Pilot Projects; Plasma; Proteins; Regression analysis; rheumatoid arthritis (RA); RNA, Messenger; RNA, Messenger - analysis; THP-1 Cells; atherosclerosis; lipoprotein a (Lp(a)); liquid chromatography/mass spectrometry (LC/MS); rheumatoid arthritis (RA); H5; electronegative subfractions of HDL; high-density lipoprotein (HDL)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222111419

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-1β and IL-8 mRNA in H5-treated (mean ± SD, 4.45 ± 1.22 folds, 6.02 ± 1.43-folds, respectively) than H1-treated monocytes (0.89 ± 0.18-folds, 1.03 ± 0.26-folds, respectively, both p < 0.001). In macrophages, H5 upregulated the mRNA and protein expression of IL-1β 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.