Simvastatin Efficiently Lowers Small LDL-IgG Immune Complex Levels: A Therapeutic Quality beyond the Lipid-Lowering Effect

• Published in: PloS one Vol. 11; no. 2; p. e0148210
• Main Authors: Hörl, Gerd, Froehlich, Harald, Ferstl, Ulrika, Ledinski, Gerhard, Binder, Josepha, Cvirn, Gerhard, Stojakovic, Tatjana, Trauner, Michael, Koidl, Christoph, Tafeit, Erwin, Amrein, Karin, Scharnagl, Hubert, Jürgens, Günther, Hallström, Seth
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.02.2016; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Antigen-Antibody Complex - blood; Antigen-Antibody Complex - immunology; Antigen-antibody complexes; Antigens; Apolipoproteins; Apolipoproteins B - blood; Arteriosclerosis; Atherosclerosis; Autoimmune diseases; Biology and Life Sciences; Chemistry; Cholesterol; Cholesterol, LDL - blood; Cholesterol, LDL - immunology; Chromatography; Coronary artery; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - drug therapy; Coronary Restenosis - blood; Coronary Restenosis - drug therapy; Densitometers; Density; Density gradients; Dissociation; Female; Fluorescence; Glycoproteins; Heart diseases; High performance liquid chromatography; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immune response; Immunoassay; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - immunology; Immunoglobulins; Immunology; Internal medicine; Laboratories; Light scattering; Lipids; Lipoproteins (low density); Liquid chromatography; Low density lipoprotein; Low density lipoproteins; Lupus; Male; Malondialdehyde; Malondialdehyde - blood; Measurement; Medicine; Medicine and Health Sciences; Middle Aged; Monoclonal antibodies; Observations; Oxidation; Particle density (concentration); Particle size distribution; Patient outcomes; Patients; Peripheral Arterial Disease - blood; Peripheral Arterial Disease - drug therapy; Photon correlation spectroscopy; Physical Sciences; Physiology; Plasma levels; Polyethylene; Polyethylene glycol; Polyethylenes; Research and Analysis Methods; Salts; Simvastatin; Simvastatin - therapeutic use; Size distribution; Size exclusion chromatography; Statins; Therapy; Ultracentrifugation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148210

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.