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

• Hs3st1−/− mice had increased LPS-lethality due to enhanced TNF-sensitivity.
• HSAT + is essential for AT's anti- but not pro- inflammatory effects.
• The rs16881446G allele associated with reduced HS3ST1 expression.
• rs16881446G/G associated with cardiovascular disease severity and events.
• An HSAT +·AT pathway may protect against acute and chronic inflammatory disorders.

The HS3ST1 gene controls endothelial cell production of HSAT + – a form of heparan sulfate containing a specific pentasaccharide motif that binds the anticoagulant protein antithrombin (AT). HSAT + has long been thought to act as an endogenous anticoagulant; however, coagulation was normal in Hs3st1−/− mice that have greatly reduced HSAT + (HajMohammadi et al., 2003). This finding indicates that HSAT + is not essential for AT's anticoagulant activity. To determine if HSAT + 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, HSAT + selectively mediates AT's anti-inflammatory activity; in the absence of HSAT +, AT's pro-inflammatory effects predominate. To explore if the anti-inflammatory action of HSAT + 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 rs16881446G/G genotype independently associated with the severity of coronary artery disease and atherosclerotic cardiovascular events. In primary endothelial cells, the rs16881446G 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.