title: Effect of carboxyl-reduced heparin on the growth inhibition of bovine pulmonary artery smooth muscle cells.
abstract: Heparin (HP) inhibits the proliferation of bovine pulmonary artery smooth muscle cells (BPASMC's), among other cell types in vitro. In order to develop a potential therapeutic agent to reverse vascular remodeling, we are involved in deciphering the relationship between the native HP structure and its antiproliferative potency. We have previously reported the influence of the molecular size and the effects of various O-sulfo and N-acetyl groups of HP on growth-inhibitory activity. In this study, to understand the influence of carboxyl groups in the HP structure required for endogenous activity, a chemically modified derivative of native HP was prepared by converting the carboxyl groups of hexuronic acid residues in HP to primary hydroxyl groups. This modification procedure involves the treatment of HP with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide followed by reduction with NaBH(4) to yield carboxyl-reduced heparin (CR-HP). When compared to the antiproliferative potency of native HP on cultured BPASMC's at three dose levels (1, 10, and 100 microg/mL), the CR-HP showed significantly less potency at all the doses. These results suggest that hexuronic acid residues in both major and variable sequences in HP are essential for the antiproliferative properties of native HP.
authors.affiliation: Department of Medicine, Pulmonary/Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Hgarg@partners.org
authors.forename: Hari G
authors.initials: HG
authors.lastname: Garg
authors.forename: Hicham
authors.initials: H
authors.lastname: Mrabat
authors.forename: Lunyin
authors.initials: L
authors.lastname: Yu
authors.forename: Craig
authors.initials: C
authors.lastname: Freeman
authors.forename: Boyangzi
authors.initials: B
authors.lastname: Li
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hales
mesh_terms: D000818:Animals; D001894:Borohydrides / Q000737:chemistry; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D006603:Hexuronic Acids / Q000737:chemistry; D006878:Hydroxides / Q000737:chemistry; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects*; D010084:Oxidation-Reduction; D011651:Pulmonary Artery / Q000166:cytology*
chemical_list: D001894:Borohydrides; D006603:Hexuronic Acids; D006878:Hydroxides; C025364:sodium borohydride; D006493:Heparin; C031356:hydroxide ion
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