title: Subendothelial retention of lipoprotein (a). Evidence that reduced heparan sulfate promotes lipoprotein binding to subendothelial matrix.
abstract: Vessel wall subendothelial extracellular matrix, a dense mesh formed of collagens, fibronectin, laminin, and proteoglycans, has important roles in lipid and lipoprotein retention and cell adhesion. In atherosclerosis, vessel wall heparan sulfate proteoglycans (HSPG) are decreased and we therefore tested whether selective loss of HSPG affects lipoprotein retention. A matrix synthesized by aortic endothelial cells and a commercially available matrix (Matrigel; , Rutherford, NJ) were used. Treatment of matrix with heparinase/heparitinase (1 U/ml each) increased LDL binding by approximately 1.5-fold. Binding of lipoprotein (a) [Lp(a)] to both subendothelial matrix and Matrigel(R) increased 2-10-fold when the HSPG were removed by heparinase treatment. Incubation of endothelial cells with oxidized LDL (OxLDL) or lysolecithin resulted in decreased matrix proteoglycans and increased Lp(a) retention by matrix. The effect of OxLDL or lysolecithin on endothelial PG was abolished in the presence of HDL. The decrease in matrix HSPG was associated with production of a heparanase-like activity by OxLDL-stimulated endothelial cells. To test whether removal of HSPG exposes fibronectin, a candidate Lp(a) binding protein in the matrix, antifibronectin antibodies were used. The increased Lp(a) binding after HSPG removal was inhibited 60% by antifibronectin antibodies. Similarly, the increased Lp(a) binding to matrix from OxLDL-treated endothelial cells was inhibited by antifibronectin antibodies. We hypothesize that atherogenic lipoproteins stimulate endothelial cell production of heparanase. This enzyme reduces HSPG which in turn promotes Lp(a) retention.
authors.affiliation: Division of Preventive Medicine and Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA. ps42@columbia.edu
authors.forename: S
authors.initials: S
authors.lastname: Pillarisetti
authors.forename: L
authors.initials: L
authors.lastname: Paka
authors.forename: J C
authors.initials: JC
authors.lastname: Obunike
authors.forename: L
authors.initials: L
authors.lastname: Berglund
authors.forename: I J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002808:Chondroitin Lyases / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D017270:Lipoprotein(a) / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D010084:Oxidation-Reduction; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism*
chemical_list: D002808:Chondroitin Lyases; D003094:Collagen; D004338:Drug Combinations; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate; D007797:Laminin; D017270:Lipoprotein(a); D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; C059485:matrigel