Abstract
We investigated a polyethylene glycol non-precipitable low-density lipoprotein (LDL) subfraction targeted by IgG and the influence of statin therapy on plasma levels of these small LDL-IgG-immune complexes (LDL-IgG-IC). LDL-subfractions were isolated from 6 atherosclerotic subjects and 3 healthy individuals utilizing iodixanol density gradient ultracentrifugation. Cholesterol, apoB and malondialdehyde (MDA) levels were determined in each fraction by enzymatic testing, dissociation-enhanced lanthanide fluorescence immunoassay and high-performance liquid chromatography, respectively. The levels of LDL-IgG-IC were quantified densitometrically following lipid electrophoresis, particle size distribution was assessed with dynamic light scattering and size exclusion chromatography. The influence of simvastatin (40 mg/day for three months) on small LDL-IgG-IC levels and their distribution among LDL-subfractions (salt gradient separation) were investigated in 11 patients with confirmed coronary artery disease (CAD). We demonstrate that the investigated LDL-IgG-IC are small particles present in atherosclerotic patients and healthy subjects. In vitro assembly of LDL-IgG-IC resulted in particle density shifts indicating a composition of one single molecule of IgG per LDL particle. Normalization on cholesterol levels revealed MDA values twice as high for LDL-subfractions rich in small LDL-IgG-IC if compared to dominant LDL-subfractions. Reactivity of affinity purified small LDL-IgG-IC to monoclonal antibody OB/04 indicates a high degree of modified apoB and oxidative modification. Simvastatin therapy studied in the CAD patients significantly lowered LDL levels and to an even higher extent, small LDL-IgG-IC levels without affecting their distribution. In conclusion simvastatin lowers levels of small LDL-IgG-IC more effectively than LDL-cholesterol and LDL-apoB levels in atherosclerotic patients. This antiatherogenic effect may additionally contribute to the known beneficial effects of this drug in the treatment of atherosclerosis.
Highlights
Development and progression of atherosclerosis are associated with elevated levels of low-density lipoprotein (LDL) and oxidized LDL [1]
A hallmark of atherosclerosis is the uptake of modified forms of LDL via scavenger receptors leading to the transformation of macrophages and smooth muscle cells into foam cells [2]
We observed a significant increase in pellet cholesterol after storage of serum at 4°C and concomitantly, a storage-time-dependent decrease in cholesterol of LDL-subfractions isolated from polyethylene glycol (PEG) supernatants
Summary
Development and progression of atherosclerosis are associated with elevated levels of LDL and oxidized LDL (oxLDL) [1]. A hallmark of atherosclerosis is the uptake of modified forms of LDL via scavenger receptors leading to the transformation of macrophages and smooth muscle cells into foam cells [2]. LDL particles are modified in arterial intima and in the circulation by several mechanisms, such as glycation, lipolysis, aggregation and oxidation [3]. Innate and adaptive immune mechanisms play a critical role in atherogenesis. Autoimmune reactions targeting modified LDL particles are considered to contribute to atherogenesis as the resulting LDL-IgG-IC are effectively taken up by macrophages and other cell types via Fcγ-receptors [5, 6, 9, 10]
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