Sulfation patterns in heparin and heparan sulfate: effects on the proliferation of bovine pulmonary artery smooth muscle cells.
Heparin's (HP's) antiproliferative effect on smooth muscle cells is potentially important in defining new approaches to treat pulmonary hypertension. The commercially available HP and heparan sulfate (HS) are structurally heterogenous polymers. In order to examine which sulfonate groups are required for endogenous antiproliferative activity, we prepared the following six chemically modified porcine mucosal HP and HS, which fell into three groups. One group consisted of fully O-sulfonated-N-acetylated, the second group consisted of de-N-sulfonated and re-N-acetylated, and the third group consisted of 6-O-desulfonated HP and HS derivatives. These six preparations were assayed for their antiproliferative potency on bovine pulmonary artery smooth muscle cells. The results of this assay show that (a) over-O-sulfonation of both HP and HS increases antiproliferative activity, (b) substitution of hexosamine with N-acetyl diminishes antiproliferative activity in both HP and HS, and (c) 6-O-desulfonation of HP and HS diminishes antiproliferative potency. Surprisingly, the type of uronic acid residue present at a given level of sulfation is unimportant for antiproliferative potency. In conclusion, only the level of O- and N-sulfo group substitution correlates well with HP and HS antiproliferative activity.
Garg
Hari G
HG
Pulmonary/Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. HGARG@PARTNERS.ORG
Yu
Lunyin
L
Hales
Charles A
CA
Toida
Toshihiko
T
Islam
Tasneem
T
Linhardt
Robert J
RJ
D000818:Animals; D002240:Carbohydrate Sequence; D002417:Cattle; D018929:Cell Culture Techniques / Q000379:methods; D002455:Cell Division; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects; D013464:Sulfuric Acids / Q000032:analysis
D006493:Heparin; D006497:Heparan Sulfate; D013464:Sulfuric Acids