Internal Med Medical News about systemic lupus;cholesterol homeostasis

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Plasma from systemic lupus patients compromises cholesterol homeostasis: A potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease
Rheumatology International, 06/29/09

Reiss AB et al. – Study provides evidence for impaired cholesterol homeostasis in systemic lupus erythematosus (SLE) and of immune involvement in atherogenesis. Strategies to inhibit or reverse arterial cholesterol accumulation may benefit SLE patients.

Methods

Aim was to determine whether lupus plasma impacts expression of cholesterol 27-hydroxylase, an anti-atherogenic cholesterol-degrading enzyme that promotes cellular cholesterol efflux
THP-1 human monocytes and primary human aortic endothelial cells (HAEC) were used for this study
THP-1 monocytes and HAEC were incubated in medium containing SLE patient plasma or healthy control human plasma (CHP)

Results

SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47 ± 8%, and in HAEC by 51 ± 5.5%
THP-1 macrophages were incubated in 25% lupus plasma or CHP and cholesterol-loaded (50 µg/ml acetylated low density lipoprotein)
Lupus plasma more than doubled macrophage foam cell transformation

Exclusive Author Commentary
Allison B. Reiss, M.D., 06/30/09

It is well known that persons with SLE are at high risk for accelerated atherosclerosis. Although the mechanisms that lead to this life-threatening situation are unclear, inflammation is thought to play a crucial role. This paper examines the problem from a novel angle by demonstrating that factors in the circulation of SLE patients affect cholesterol outflow pathways in cells that are involved in the atherosclerotic process at a local level within the vulnerable arterial wall. Both arterial endothelial lining cells and monocytes/macrophages are normally active participants in defending against the arterial lumen narrowing that occurs with lipid overload and foam cell formation. Our in vitro studies using control plasma and plasma isolated from persons with SLE indicates that the SLE plasma disarms the natural defenses of cultured human monocytes/macrophages and primary endothelium by suppressing the expression of cholesterol 27-hydroxylase, a cholesterol-metabolizing enzyme that also promotes cellular cholesterol efflux. Upon pre-incubation with interferon-gamma receptor blocking antibody, the pro-atherogenic potency of the lupus plasma is lost, suggesting that the actions of this inflammatory cytokine are, at least in part, responsible for the negative effect of lupus plasma on reverse cholesterol transport. Further studies are ongoing to better define the participants in this process with the hope that these findings can lead to targeted therapies for atherosclerosis in the autoimmune setting. (A. Reiss)

It is inarguable that SLE is characterized by precocious atherosclerosis so what is at issue is the relative contributions of traditional cardiac risk factors (e.g. hypertension, diabetes, elevated LDL, cigarette smoking, sedentary life style) versus the immune mediated inflammatory processes that accompany disease exacerbation. This report identifies at least one mechanism whereby disease activity could promote atherogenesis and is concordant with other data from participating laboratories that endothelial cell activation is associated with SLE and can be a predicate for vascular injury including atherosclerotic. This data is also consistent with the finding by Roman [NEJM] et al that more aggressive management of disease (i.e. use of steroids and cytotoxics) is associated with less carotid artery disease and argues for tight control of the SLE disease process similar to the current recommendations for diabetes. (H.M. Belmont)