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 inh ibition causes mast cells to produce heparins with high affinity for a ntithrombin (AT). We have cultured endothelial cells in media suppleme nted with short chain fatty acids and have found that isobutyric, prop ionic and valeric acids cause significant increases in endothelial bin ding 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-treatmen t of the cells with heparinase. These findings suggest that inhibition of N-deacetylation in heparan biosynthesis affects sulfation and resu lts in the and conformational changes within the heparan domain that b inds AT to endothelial plasma membranes. These changes also were assoc iated with up-regulation of the intercellular adhesion molecule-1, whi ch is a marker of endothelial activation.