A synthetic heparin-mimicking polyanionic compound binds to the LDL receptor-related protein and inhibits vascular smooth muscle cell proliferation

A synthetic heparin-mimicking polyaromatic anionic compound RG-13577 (polym er of 4-hydroxyphenoxy acetic acid and formaldehyde ammonium salt, Mr simil ar to 5800) exhibits specific binding to vascular smooth muscle cells (SMCs ) and inhibits their proliferative response to growth promoting factors. Re ceptor binding of C-14-RG-13577 was efficiently competed by apolipoprotein E3 (apoE), lactoferrin, and the LRP (LDL receptor-related protein) receptor associated 39 kDa protein (RAP). Unlike cell surface binding of apoE, bind ing of RG-13577 to SMCs was not affected by heparin, heparan sulfate degrad ing enzymes, or low density lipoprotein (LDL). Moreover, wild-type and hepa ran sulfate-deficient Chinese hamster ovary (CHO) cells, as well as normal- and LDL receptor negative- human skin fibroblasts bind RG-13577, but not a poE, to a similar extent. On the other hand, homozygous mouse embryonic fib roblasts deficient in the LDL receptor-related protein (LRP) expressed a ma rkedly reduced binding of RG-13577 as compared to normal mouse embryonic fi broblasts. These results indicate that RG-13577 and related compounds bind to the LRP receptor on the surface of vascular SMCs. Addition of lactoferri n to cultured SMCs protected the cells against the antiproliferative effect of compound RG-13577, suggesting that this inhibition is mediated by RG-13 577 binding to LRP receptors on the SMC surface. Altogether, we have identi fied a series of synthetic polyaromatic anionic molecules that exhibit spec ific binding to LRP and therby exert an antiproliferative effect on vascula r SMCs. These compounds are applied to suppress SMC proliferation associate d with restenosis and accelerated atherosclerosis. (C) 2001 Wiley-Liss. Inc .