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

PLoS One. 2016 Feb 3;11(2):e0148210. doi: 10.1371/journal.pone.0148210. eCollection 2016.

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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigen-Antibody Complex / blood*
  • Antigen-Antibody Complex / immunology
  • Apolipoproteins B / blood
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / immunology
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / drug therapy*
  • Coronary Restenosis / blood
  • Coronary Restenosis / drug therapy*
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Male
  • Malondialdehyde / blood
  • Middle Aged
  • Peripheral Arterial Disease / blood
  • Peripheral Arterial Disease / drug therapy*
  • Simvastatin / therapeutic use*

Substances

  • Antigen-Antibody Complex
  • Apolipoproteins B
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Immunoglobulin G
  • Malondialdehyde
  • Simvastatin

Grants and funding

The authors have no support or funding to report.