© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Reduction of arteriosclerotic nanoplaque formation and size by fluvastatin in a receptor-based biosensor model
aInstitute of Physiology, Biophysical Research Group, The Free University of Berlin, Arnimallee 22, D-14195 Berlin, Germany
bClinical Research, Novartis Pharma GmbH, D-90327 Nürnberg, Germany
cInstitute for Surface Chemistry, Royal Institute of Technology, SE-10044 Stockholm, Sweden
dInstitute for Arteriosclerosis Research, University of Münster, D-48149 Münster, Germany
eInstitute of Clinical Chemistry, University Clinic Freiburg, D-79106 Freiburg, Germany
siegelg{at}zedat.fu-berlin.de
* Corresponding author. Tel.: +49-30-8445-1685; fax: +49-30-8445-1684.
Proteoheparan sulfate can be adsorbed onto a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques suggesting that HDL has a high binding affinity and a protective effect on interfacial heparan sulfate proteoglycan layers with respect to LDL and Ca2+ complexation. LDL was found to be deposited strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca2+, apparently through complex formation ‘proteoglycan–low density lipoprotein–calcium’. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. In a receptor-based biosensor application, this system was tested on its reliability to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The VLDL/IDL/LDL and VLDL/IDL/LDL/HDL plasma fractions from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed the start of arteriosclerotic nanoplaque formation at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. Nanoplaque formation and size of the HDL-containing lipid fraction remained well below that of the LDL-containing lipid fraction. Fluvastatin, whether applied acutely to the patient (one single 80 mg slow release matrix tablet) or in a 2-month medication regimen, markedly slowed down this process of ternary aggregational nanoplaque build-up and substantially inhibited nanoplaque size development at all Ca2+ concentrations used. The acute action gave no significant change in lipid concentrations of the patient. Furthermore, after nanoplaque generation, fluvastatin, similar to HDL, was able to reduce nanoplaque formation and size. These immediate effects of fluvastatin have to be taken into consideration when interpreting the clinical outcome of long-term studies.
KEYWORDS Atherosclerosis; CSE inhibitor; Ellipsometry; Lipoproteins; Proteoglycan receptor