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Liver X receptor agonists inhibit tissue factor expression in macrophages
Naoki Terasaka1, Ayano Hiroshima, Akiko Ariga
1Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan. terasa@shina.sankyo.co.jp
The FEBS Journal
|March 9, 2005
Summary
Activation of liver X receptors (LXRs) suppresses tissue factor (TF) expression, a key factor in blood clot formation. This finding suggests LXR agonists may offer a new approach to treating vascular diseases like atherosclerosis.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Research
Background:
- Tissue factor (TF) initiates coagulation cascades and is implicated in thrombus formation within atherosclerotic lesions.
- Pro-inflammatory stimuli like lipopolysaccharide (LPS) induce macrophage TF expression.
Purpose of the Study:
- To investigate the effect of liver X receptors (LXRs) on TF expression.
- To explore the potential of LXR activation as a therapeutic strategy for vascular diseases.
Main Methods:
- Treated mouse peritoneal macrophages and human monocytes with LXR agonists (T0901317, GW3965).
- Assessed TF expression and activity.
- Utilized cotransfection assays to analyze TF promoter activity and signaling pathways (NF-kappaB).
- Evaluated LXR agonist effects in vivo using an atherosclerosis mouse model.
Main Results:
- LXR agonists significantly suppressed LPS-induced TF expression in macrophages and monocytes.
- LXR activation reduced TF promoter activity, partly via inhibition of the NF-kappaB signaling pathway.
- In vivo studies showed LXR agonists decreased TF expression in aortic lesions and other tissues.
Conclusions:
- LXR activation effectively reduces TF expression.
- This suppression mechanism, particularly through NF-kappaB inhibition, holds potential for managing atherothrombosis in vascular disease patients.