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Homocysteine inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion via nuclear
V Stangl1, C Günther, A Jarrin
1Medizinische Klinik und Poliklinik, Schwerpunkt Kardiologie, Angiologie and Pneumologie, Charité der Humboldt-Universität, Campus Mitte, Berlin, Germany. verena.stangl@charite.de
Insights
Homocysteine reduces the expression of key adhesion molecules like ICAM-1, VCAM-1, and E-selectin on endothelial cells. This finding suggests a potential therapeutic role for homocysteine in mitigating atherosclerosis development.
Area of Science:
- Cardiovascular biology
- Endothelial cell research
- Atherosclerosis pathogenesis
Background:
- Cellular adhesion molecules mediate leukocyte adherence, a key step in atherosclerosis.
- Hyperhomocysteinemia is an independent risk factor for atherosclerosis development.
Purpose of the Study:
- To investigate homocysteine's effect on endothelial adhesion molecule expression.
- To determine if homocysteine influences TNF-alpha-induced adhesion molecule upregulation.
Main Methods:
- Human umbilical vein endothelial cells were incubated with homocysteine.
- Expression of ICAM-1, VCAM-1, and E-selectin was measured.
- U-937 cell adhesion and NF-kappaB activation were assessed.
Main Results:
- Homocysteine dose-dependently reduced TNF-alpha-induced VCAM-1, E-selectin, and ICAM-1 expression.
- This effect was specific to homocysteine, not mimicked by cysteine or glutathione.
- Homocysteine attenuated U-937 cell adhesion and reduced NF-kappaB activation.
Conclusions:
- Homocysteine inhibits the expression of key endothelial adhesion molecules.
- NF-kappaB inhibition is a likely mechanism underlying homocysteine's effect.
- Homocysteine may play a role in preventing atherosclerosis progression.
Abstract:
Cellular adhesion molecules play a pivotal role in the pathogenesis of atherosclerosis by mediating the adherence of blood leukocytes. Since hyperhomocysteinemia appears to be an independent risk factor for the development of atherosclerosis, in this study we investigated the effect of homocysteine on basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) on human umbilical-vein endothelial cells. Incubation of endothelial cells with homocysteine resulted in dose-dependent reduction in TNF-alpha-induced (5 ng/ml) expression of VCAM-1, E-selectin, and ICAM-1 (the latter less pronounced). This effect was found to be specific since other thiol compounds-cysteine and glutathione-did not mimic homocysteine activity. Homocysteine attenuated TNF-alpha-stimulated U-937 adhesion to the endothelial monolayer and reduced TNF-alpha-induced activation of the transcription factor NF-kappaB, indicating that NF-kappaB inhibition may play a role in inhibiting expression of adhesion molecules in endothelial cells.