Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004153 (
atherosclerosis
)
77,401
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. 2812 21
