Reduction of arteriosclerotic nanoplaque formation and size by fluvastatin in a receptor-based biosensor model.
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 Ca(2+) complexation. LDL was found to be deposited strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca(2+), 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 Ca(2+) concentration, with a strong increase at higher Ca(2+) 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 Ca(2+) 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.
Siegel
G
G
Institute of Physiology, Biophysical Research Group, The Free University of Berlin, Arnimallee 22, D-14195 Berlin, Germany. siegelg@zedat.fu-berlin.de
Abletshauser
C
C
Malmsten
M
M
Schmidt
A
A
Winkler
K
K
D000327:Adsorption; D015374:Biosensing Techniques; D002118:Calcium / Q000494:pharmacology; D003327:Coronary Disease / Q000097:blood* / Q000517:prevention & control*; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D000077340:Fluvastatin; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008859:Microscopy, Polarization; D013997:Time Factors
D005229:Fatty Acids, Monounsaturated; D019812:Heparan Sulfate Proteoglycans; D000960:Hypolipidemic Agents; D007211:Indoles; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000077340:Fluvastatin; D002118:Calcium