We here investigated the functional effect of 4-O-methylgallic acid (4-OMGA), a major metabolite of gallic acid abundant in red wine, on vascular inflammation and its action mechanism. 4-OMGA inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) stimulated with tumor necrosis factor-α (TNF-α), resulting in the suppression of leukocyte adhesion to HUVECs. In addition, 4-OMGA inhibited the promoter activities of ICAM-1 and VCAM-1 and the activity of nuclear factor-κB (NF-κB) without affecting cytosolic IκB kinase (IKK) activation, inhibitor of κB (IκB) phosphorylation and degradation, and nuclear translocation of NF-κB. This compound did not alter nitric oxide (NO) generation, but inhibited reactive oxygen species (ROS) production in TNF-α-stimulated HUVECs, suggesting that NO and ROS are not involved in 4-OMGA-mediated inhibition of NF-κB activity. Moreover, 4-OMGA directly blocked the binding activity of NF-κB to its consensus DNA oligonucleotide, when pre-incubated with the nuclear extract from TNF-α-stimulated HUVECs, but not with the oligonucleotide alone. This inhibition was completely abolished by the addition of dithiothreitol. 4-OMGA exhibits an anti-inflammatory property by interfering with the formation of the NF-κB-DNA complex in the nuclei through direct and redox-sensitive interactions and may play an important role in the prevention of inflammatory responses such as the atherosclerotic process.
Bibliographical noteFunding Information:
This work was supported by Vascular System Research Center grant from KOSEF.
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