The effect of an HMG-CoA reductase inhibitor on arteriosclerotic nanoplaque formation and size in a biosensor model.
Proteoheparan sulfate can be adsorbed to 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. Low-density lipoprotein (LDL) was found to deposit strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca(2+), apparently through complex formation 'proteoglycan-LDL-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. HDL bound to heparan sulfate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition and to disrupt newly formed nanoplaques. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. The molecular arteriosclerosis model was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL and VLDL/IDL/LDL/HDL plasma fractions from a high-risk patient with dyslipoproteinemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already 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-months 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 resulted without any 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 while interpreting the clinical outcome of long-term studies.
Siegel
G
G
Institute of Physiology, Biophysical Research Group, The Free University of Berlin, Arnimallee 22, DE-14195, Berlin, Germany. siegelg@zedat.fu-berlin.de
Abletshauser
C
C
Malmsten
M
M
Klüssendorf
D
D
D000327:Adsorption; D001161:Arteriosclerosis / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D015374:Biosensing Techniques / Q000379:methods*; D002114:Calcinosis / Q000097:blood / Q000188:drug therapy; D002118:Calcium / Q000378:metabolism; D020099:Coated Materials, Biocompatible / Q000138:chemical synthesis / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D000077340:Fluvastatin; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood* / Q000187:drug effects; D008422:Materials Testing; D008954:Models, Biological; D010316:Particle Size; D012822:Silicon Dioxide / Q000378:metabolism; D013499:Surface Properties / Q000187:drug effects; D016896:Treatment Outcome
D020099:Coated Materials, Biocompatible; D005229:Fatty Acids, Monounsaturated; D019812:Heparan Sulfate Proteoglycans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D007211:Indoles; D008074:Lipoproteins; D000077340:Fluvastatin; D012822:Silicon Dioxide; D002118:Calcium