Abstract
L5, the most negatively charged subfraction of low-density lipoprotein (LDL), is implicated in atherogenesis, but the pathogenic association is relatively unexplored in patients with rheumatoid arthritis (RA). We examined the role of L5 LDL in macrophage foam cell formation and the association of L5 with CD11c expression in THP-1 cells and RA patients. Using quantitative real-time PCR, we determined mRNA expression levels of ITGAX, the gene for CD11c, a marker associated with vascular plaque formation and M1 macrophages in atherogenesis, in 93 RA patients. We also examined CD11c expression on THP-1 cells treated with L5 by flow cytometry analysis and the plasma levels of inflammatory mediators using a magnetic bead array. We found a dose-dependent upregulation of foam cell formation of macrophages after L5 treatment (mean ± SEM, 12.05 ± 2.35% in L5 (10 µg/mL); 50.13 ± 3.9% in L5 (25 µg/mL); 90.69 ± 1.82% in L5 (50 µg/mL), p < 0.01). Significantly higher levels of CD11c expression were observed in 30 patients with a high percentage of L5 in LDL (L5%) (0.0752 ± 0.0139-fold) compared to 63 patients with normal L5% (0.0446 ± 0.0054-fold, p < 0.05). CD11c expression levels were increased in the L5-treated group (30.00 ± 3.13% in L5 (10 µg/mL); 41.46 ± 2.77% in L5 (50 µg/mL), p < 0.05) and were positively correlated with plasma levels of interleukin (IL)-6 and IL-8. L5 augmented the expression of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) on monocytes and macrophages. Our findings suggest that L5 may promote atherogenesis by augmenting macrophage foam cell formation, upregulating CD11c expression, and enhancing the expression levels of atherosclerosis-related mediators.
Highlights
Atherosclerosis, a chronic inflammatory process, is characterized by atheromatous plaque buildup and associated with increased cardiovascular disease (CVD) risk [1]
We found no significant differences between Rheumatoid arthritis (RA) patients with high L5% and normal L5% in demographic variables, clinical characteristics, the proportion of positivity for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), disease activity scores, the proportion of comorbidities, or medication use
High L5% is defined as plasma L5 proportion above 1.8%. b p < 0.05 and c p < 0.01 vs. patients with normal L5%, as determined by using the Mann–Whitney U test. d Included two patients with acute ST-segment elevation myocardial infarction and four with ischemic stroke; e included two patients with acute ST-segment elevation myocardial infarction and two with ischemic stroke; BMI: Body mass index; ACPA: Anti-citrullinated peptide antibodies; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; DAS28: Disease activity score for 28-joints; conventional synthetic disease-modifying anti-rheumatic drug (csDMARD): Conventional synthetic disease-modifying anti-rheumatic drugs; tumor necrosis factor-α (TNF-α): Tumor necrosis factor-α; IL-6: Interleukin-6; total cholesterol (TC): Total cholesterol; high-density lipoprotein-cholesterol (HDL-C): High-density lipoprotein cholesterol; low-density lipoprotein (LDL)-C: Low-density lipoprotein cholesterol; atherogenic index is the ratio of TC/HDL-C; CVD: Cerebrovascular/cardiovascular disease
Summary
Atherosclerosis, a chronic inflammatory process, is characterized by atheromatous plaque buildup and associated with increased cardiovascular disease (CVD) risk [1]. The high CVD burden in RA patients would be explained by traditional CV risk factors and systemic inflammation in this disease [6,7]. Inflammatory mediators such as interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) are commonly involved in the pathogenesis of RA-related atherosclerosis [8,9,10,11,12]. We recently reported that an elevated the percentage of L5 in LDL (L5%) is associated with an increased CVD risk in patients with RA or systemic lupus erythematosus [15,16]. It is important to study the role of L5 in foam cell formation in macrophages
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