title: Anionic biopolyelectrolytes of the syndecan/perlecan superfamily: physicochemical properties and medical significance.
abstract: In the review article presented here, we demonstrate that the connective tissue is more than just a matrix for cells and a passive scaffold to provide physical support. The extracellular matrix can be subdivided into proteins (collagen, elastin), glycoconjugates (structural glycoproteins, proteoglycans) and glycosaminoglycans (hyaluronan). Our main focus rests on the anionic biopolyelectrolytes of the perlecan/syndecan superfamily which belongs to extracellular matrix and cell membrane integral proteoglycans. Though the extracellular domain of the syndecans may well be performing a structural role within the extracellular matrix, a key function of this class of membrane intercalated proteoglycans may be to act as signal transducers across the plasma membrane and thus be more appropriately included in the group of cell surface receptors. Nevertheless, there is a continuum in functions of syndecans and perlecans, especially with respect to their structural role and biomedical significance. HS/CS proteoglycans are receptor sites for lipoprotein binding thus intervening directly in lipid metabolism. We could show that among all lipoproteins, HDL has the highest affinity to these proteoglycans and thus instals a feedforward forechecking loop against atherogenic apoB100 lipoprotein deposition on surface membranes and in subendothelial spaces. Therefore, HDL is not only responsible for VLDL/IDL/LDL cholesterol exit but also controls thoroughly the entry. This way, it inhibits arteriosclerotic nanoplaque formation. The ternary complex 'lipoprotein receptor (HS/CS-PG) - lipoprotein (LDL, oxLDL, Lp(a)) - calcium' may be interpreted as arteriosclerotic nanoplaque build-up on the molecular level before any cellular reactivity, possibly representing the arteriosclerotic primary lesion combined with endothelial dysfunction. With laser-based ellipsometry we could demonstrate that nanoplaque formation is a Ca(2+)-driven process. In an in vitro biosensor application of HS-PG coated silica surfaces we tested nanoplaque formation and size in clinical trials with cardiovascular high-risk patients who underwent treatment with ginkgo or fluvastatin. While ginkgo reduced nanoplaque formation (size) by 14.3% (23.4%) in the isolated apoB100 lipid fraction at a normal blood Ca(2+) concentration, the effect of the statin with a reduction of 44.1% (25.4%) was more pronounced. In addition, ginkgo showed beneficial effects on several biomarkers of oxidative stress and inflammation. Besides acting as peripheral lipoprotein binding receptor, HS/CS-PG is crucially implicated in blood flow sensing. A sensor molecule has to fulfil certain mechanochemical and mechanoelectrical requirements. It should possess viscoelastic and cation binding properties capable of undergoing conformational changes caused both mechanically and electrostatically. Moreover, the latter should be ion-specific. Under no-flow conditions, the viscoelastic polyelectrolyte at the endothelium - blood interface assumes a random coil form. Blood flow causes a conformational change from the random coil state to the directed filament structure state. This conformational transition effects a protein unfurling and molecular elongation of the GAG side chains like in a 'stretched' spring. This configuration is therefore combined with an increase in binding sites for Na(+) ions. Counterion migration of Na(+) along the polysaccharide chain is followed by transmembrane Na(+) influx into the endothelial cell and by endothelial cell membrane depolarization. The simultaneous Ca(2+) influx releases NO and PGI2, vasodilatation is the consequence. Decrease in flow reverses the process. Binding of Ca(2+) and/or apoB100 lipoproteins (nanoplaque formation) impairs the flow sensor function. The physicochemical and functional properties of proteoglycans are due to their amphiphilicity and anionic polyelectrolyte character. Thus, they potently interact with cations, albeit in a rather complex manner. Utilizing (23)Na(+) and (39)K(+) NMR techniques, we could show that, both in HS-PG solutions and in native vascular connective tissue, the mode of interaction for monovalent cations is competition. Mg(2+) and Ca(2+) ions, however, induced a conformational change leading to an increased allosteric, cooperative K(+) and Na(+) binding, respectively. Since extracellular matrices and basement membranes form a tight-fitting sheath around the cell membrane of muscle and Schwann cells, in particular around sinus node cells of the heart, and underlie all epithelial and endothelial cell sheets and tubes, a release of cations from or an adsorption to these polyanionic macromolecules can transiently lead to fast and drastic activity changes in these tiny extracellular tissue compartments. The ionic currents underlying pacemaker and action potential of sinus node cells are fundamentally modulated. Therefore, these polyelectrolytic ion binding characteristics directly contribute to and intervene into heart rhythm.
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany; University of Uppsala Biomedical Center, 751 23 Uppsala, Sweden. Electronic address: guenter.siegel@charite.de.
authors.forename: G
authors.initials: G
authors.lastname: Siegel
authors.affiliation: University of Uppsala Biomedical Center, 751 23 Uppsala, Sweden; Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Malmsten
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Ermilov
mesh_terms: D000838:Anions / Q000737:chemistry; D001704:Biopolymers / Q000737:chemistry*; D002627:Chemistry, Physical; D004573:Electrolytes / Q000737:chemistry; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry*; D006801:Humans; D053667:Syndecans / Q000737:chemistry*
chemical_list: D000838:Anions; D001704:Biopolymers; D004573:Electrolytes; D019812:Heparan Sulfate Proteoglycans; D053667:Syndecans; C071927:perlecan
keywords: Blood flow sensor; Cation binding; Lipoprotein binding receptor; Smooth and heart muscle rhythmogenesis; Syndecan/perlecan physicochemistry and molecular biology; Tumour invasion and metastasis