HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis

The HS3ST1 gene controls endothelial cell production of HS^AT+ - a form of heparan sulfate containing a specific pentasaccharide motif that binds the anticoagulant protein antithrombin (AT). HS^AT+ has long been thought to act as an endogenous anticoagulant; however, coagulation was normal in Hs3st1^-/- mice that have greatly reduced HS^AT+ (HajMohammadi et al., 2003). This finding indicates that HS^AT+ is not essential for AT's anticoagulant activity. To determine if HS^AT+ is involved in AT's poorly understood inflammomodulatory activities, Hs3st1^-/- and Hs3st1^+/+ mice were subjected to a model of acute septic shock. Compared with Hs3st1^+/+ mice, Hs3st1^-/- mice were more susceptible to LPS-induced death due to an increased sensitivity to TNF. For Hs3st1^+/+ mice, AT treatment reduced LPS-lethality, reduced leukocyte firm adhesion to endothelial cells, and dilated isolated coronary arterioles. Conversely, for Hs3st1^-/- mice, AT induced the opposite effects. Thus, in the context of acute inflammation, HS^AT+ selectively mediates AT's anti-inflammatory activity; in the absence of HS^AT+, AT's pro-inflammatory effects predominate. To explore if the anti-inflammatory action of HS^AT+ also protects against a chronic vascular-inflammatory disease, atherosclerosis, we conducted a human candidate-gene association study on >2000 coronary catheterization patients. Bioinformatic analysis of the HS3ST1 gene identified an intronic SNP, rs16881446, in a putative transcriptional regulatory region. The rs16881446^G/G genotype independently associated with the severity of coronary artery disease and atherosclerotic cardiovascular events. In primary endothelial cells, the rs16881446^G allele associated with reduced HS3ST1 expression. Together with the mouse data, this leads us to conclude that the HS3ST1 gene is required for AT's anti-inflammatory activity that appears to protect against acute and chronic inflammatory disorders.