SUBENDOTHELIAL RETENTION OF LIPOPROTEIN (A) - EVIDENCE THAT REDUCED HEPARAN-SULFATE PROMOTES LIPOPROTEIN BINDING TO SUBENDOTHELIAL MATRIX

Vessel wall subendothelial extracellular matrix, a dense mesh formed o f collagens, fibronectin, laminin, and proteoglycans, has important ro les in lipid and lipoprotein retention and cell adhesion. In atheroscl erosis, vessel wall heparan sulfate proteoglycans (HSPG) are decreased and we therefore tested whether selective loss of HSPG affects lipopr otein retention. A matrix synthesized by aortic endothelial cells and a commercially available matrix (Matrigel; Becton Dickinson Inc., Ruth erford, NJ) were used. Treatment of matrix with heparinase/heparitinas e (1 U/ml each) increased LDL binding by similar to 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 treatm ent. Incubation of endothelial cells with oxidized LDL (OxLDL) or lyso lecithin resulted in decreased matrix proteoglycans and increased Lp(a ) retention by matrix. The effect of OxLDL or lysolecithin on endothel ial PG was abolished in the presence of HDL. The decrease in matrix HS PG was associated with production of a heparanase-like activity by OxL DL-stimulated endothelial cells. To test whether removal of HSPG expos es fibronectin, a candidate Lp(a) binding protein in the matrix, antif ibronectin antibodies were used. The increased Lp(a) binding after HSP G removal was inhibited 60% by antifibronectin antibodies. Similarly, the increased Lp(a) binding to matrix from OxLDL-treated endothelial c ells was inhibited by antifibronectin antibodies. We hypothesize that atherogenic lipoproteins stimulate endothelial cell production of hepa ranase. This enzyme reduces HSPG which in turn promotes Lp(a) retentio n.