Plasma from systemic lupus patients compromises cholesterol homeostasis: a potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease

Abstract

Atherosclerotic cardiovascular disease (ASCVD) contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Immunologic derangements may disrupt cholesterol balance in vessel wall monocytes/macrophages and endothelium. We determined whether lupus plasma impacts expression of cholesterol 27-hydroxylase, an anti-atherogenic cholesterol-degrading enzyme that promotes cellular cholesterol efflux, in THP-1 human monocytes and primary human aortic endothelial cells (HAEC). THP-1 monocytes and HAEC were incubated in medium containing SLE patient plasma or apparently healthy control human plasma (CHP). SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47 ± 8% (p < 0.008) and in HAEC by 51 ± 5.5% (n = 5, p < 0.001). THP-1 macrophages were incubated in 25% lupus plasma or CHP and cholesterol-loaded (50 µg ml−1 acetylated low density lipoprotein). Lupus plasma more than doubled macrophage foam cell transformation (74 ± 3% vs.35 § 3% for CHP, n = 3, p < 0.001). Impaired cholesterol homeostasis in SLE provides further evidence of immune involvement in atherogenesis. Strategies to inhibit or reverse arterial cholesterol accumulation may benefit SLE patients.

The Effect of A2A Adenosine Receptor Activation on C-C Chemokine Receptor 7 Expression in Human THP1 Macrophages During Inflammation

“…Prior work demonstrates that adenosine A 2A receptor activation diminishes foam cell formation not only by increasing ABCA1 expression but by increasing its function as well [12, 36–39]. We now provide further evidence that adenosine and its receptors might play a beneficial role in atherosclerosis by inhibiting recruitment of macrophages to atherosclerotic plaques.…”

Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages

“…22 The present study extends our previous finding that plasma from patients with SLE augments CD36, attenuates 27-hydroxylase and increases foam cell transformation in THP-1 macrophages. 8,9 Further exploration is needed to determine the specific mediators involved in disruption of cholesterol transport in both SLE and RA. Prospective longitudinal studies should reveal whether the cholesterol metabolic profile offers predictive value in identifying RA patients with high CVD risk.…”

“…8,18 To detect CXCL16 the following primers were used: F 5′-ACTACACGACGTTCCAGCTCC-3′; R 5′-CTTTGTCCGAGGACAGTGATC-3′. Each reaction was done in triplicate for each plasma sample.…”

“…Total cell lysates were prepared as described previously. 8,9 Protein samples (20 μg/lane) were fractionated on 8% SDS-PAGE, and transferred onto a nitrocellulose membrane (Bio-Rad, Hercules, CA). The membrane was blocked for 1 h in blocking solution (5% nonfat dry milk (Bio-Rad) in 1X Tris-buffered saline/1% Tween 20 (TTBS)) and then immersed in different dilutions of primary antibody for protein detection.…”

Circulating endothelial progenitor cells are reduced in SLE in the absence of coronary artery calcification

“…We utilized electron beam computed tomography (EBCT) to demonstrate increased coronary artery calcification (CAC) in women with SLE compared to age-matched controls [2]. The increased atherosclerotic risk in SLE is not dependent on traditional cardiovascular risk factors and may be explained by chronic systemic inflammation, alterations in metabolic and cholesterol homeostasis [3] or may be related to other novel markers such as anti-phospholipid antibodies [4]. Despite these possible explanations, the underlying factors playing a role in the development of early atherosclerosis in patients with SLE remain incompletely understood.…”