Heparan-dependent endothelial antithrombin binding is increased by butyrate.
Heparin biosynthesis involves a critical early step of N-deacetylation which is inhibited by the short chain fatty acid n-butyrate. Such inhibition causes mast cells to produce heparins with high affinity for antithrombin (AT). We have cultured endothelial cells in media supplemented with short chain fatty acids and have found that isobutyric, propionic and valeric acids cause significant increases in endothelial binding of AT measured by flow cytometry, but n-butyric acid was the most effective fatty acid to increase AT binding. Such binding,was heparan sulfate-dependent, for it was decreased significantly by pre-treatment of the cells with heparinase. These findings suggest that inhibition of N-deacetylation in heparan biosynthesis affects sulfation and results in the distribution of negative charges and conformation changes within the heparan domain that binds AT to endothelial plasma membranes. These changes also were associated with up-regulation of the intercellular adhesion molecule-1, which is a marker of endothelial activation.
Justus
A C
AC
Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis 46202, USA.
Hoggatt
A M
AM
Faulk
W P
WP
D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000187:drug effects / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D019763:Heparin Lyase; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D011133:Polysaccharide-Lyases / Q000494:pharmacology
D000925:Anticoagulants; D000990:Antithrombin III; D002087:Butyrates; D020148:Butyric Acid; D006493:Heparin; D019763:Heparin Lyase; D006497:Heparan Sulfate; D018799:Intercellular Adhesion Molecule-1; D011133:Polysaccharide-Lyases