title: Biosensing of arteriosclerotic nanoplaque formation and interaction with an HMG-CoA reductase inhibitor.
abstract: Proteoheparan sulphate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. As a result of electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing one 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 high-density lipoprotein (HDL) has a high binding affinity and a protective effect on interfacial heparan sulphate proteoglycan layers with respect to low-density lipoprotein (LDL) and Ca2+ complexation. Low-density lipoprotein was found to deposit strongly at the proteoheparan sulphate-coated surface, particularly in the presence of Ca2+, 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. On the other hand, HDL bound to heparan sulphate 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. 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. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a 'nanoscopic' level under close to physiological conditions. In particular, Ca2+-promoted LDL deposition and the protective effect of HDL even at high Ca2+ and LDL concentrations agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Considering this, the system 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 plasma fraction from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. Fluvastatin, whether applied to the patient (one single 80 mg slow release matrix tablet) or acutely in the experiment (2.2 micromol L-1), markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca2+ concentrations used. This action resulted without any significant change in lipid concentrations of the patient. Furthermore, after ternary complex build-up, fluvastatin, similar to HDL, was able to reduce nanoplaque adsorption and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the clinical outcome of long-term studies.
mesh_terms: D000327:Adsorption; D001161:Arteriosclerosis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D001665:Binding Sites / Q000502:physiology; D002113:Calcification, Physiologic / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D000077340:Fluvastatin; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007211:Indoles / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D012822:Silicon Dioxide; D013997:Time Factors
chemical_list: D005229:Fatty Acids, Monounsaturated; D019812:Heparan Sulfate Proteoglycans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000077340:Fluvastatin; D012822:Silicon Dioxide; D002118:Calcium