The antiproliferative activity of arterial heparan sulfate resides in domains enriched with 2-O-sulfated uronic acid residues.
Heparan sulfate isolated from bovine arterial tissue by a multistep purification procedure or from arterial tissue proteoheparan sulfate by beta-elimination exhibits antiproliferative activity toward arterial smooth muscle cells when added to subconfluent cell cultures in a concentration of 50-100 micrograms/ml medium. Enzymatic disintegration of heparan sulfate by heparitinases I and II and isolation of the resulting oligosaccharides indicate that the antiproliferative activity of the heparan sulfate molecule resides in a sulfate-rich octa/decasaccharide domain which is separated by longer sequences of sulfate-free or sulfate-poor N-acetylglucosamine containing disaccharide units. The octa/decasaccharide fraction has a 3-4-fold higher antiproliferative activity than the native heparan sulfate molecule and contains 45% of a disulfated disaccharide which consists of 2-O-sulfated uronic acid and N-sulfated glucosamine (UA(2S)-GlcNS and 12% of a trisulfated disaccharide (UA(2S)-GlcNS(6S). A sulfate-rich hexasaccharide fraction containing 14% of the disulfated disaccharide but 18% of the trisulfated disaccharide has negligible antiproliferative activity. The results indicate the presence of specific structural determinants in the arterial heparan sulfate molecule which may have the function of an endogenous inhibitor of arterial smooth muscle cell growth.
Schmidt
A
A
Institute for Arteriosclerosis Research, University of Münster, Federal Republic of Germany.
Yoshida
K
K
Buddecke
E
E
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006131:Growth Inhibitors / Q000737:chemistry*; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006131:Growth Inhibitors; D006497:Heparan Sulfate; D009844:Oligosaccharides