Uric acid promotes chemokine and adhesion molecule production in vascular endothelium via nuclear factor-kappa B signaling.

Hyperuricemia is an important risk factor for atherosclerosis, yet the potential mechanisms are not well understood. Migration and adhesion of leukocytes to endothelial cells play key roles in initiation and development of atherosclerosis. We investigated monocyte-endothelial cell interactions and potential signaling pathways under uric acid (UA)-stimulated conditions. Primary human umbilical vein endothelial cells (HUVECs) were cultured and exposed to different concentrations of UA for various periods. Experimental hyperuricemia rat models were established. Expression of chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were evaluated. Monocyte-endothelial cell interactions were elucidated by chemotaxis and adhesion assays, and nuclear factor-kappa B (NF-κB) pathway was studied using fluorescent microscopy and electrophoretic mobility shift assay. Results showed that high concentration of UA stimulated generation of chemokines and adhesion molecules in ex vivo and in vivo experiments. Migration and adhesion of human monocytic leukemia cell line THP-1 cells to HUVECs were promoted and activated NF-κB was significantly increased. UA-induced responses were ameliorated by organic anion transporter inhibitor probenecid and NF-κB inhibitor BAY11-7082. It was also observed that human endothelial cells expressed urate transporter-1, which was not regulated by UA. High concentration of UA exerts unfavorable effects directly on vascular endothelium via the NF-κB signaling pathway, the process of which requires intracellular uptake of UA.

Liang WY ，Zhu XY ，Zhang JW ，Feng XR ，Wang YC ，Liu ML ... -  《-》

Apelin-APJ induces ICAM-1, VCAM-1 and MCP-1 expression via NF-κB/JNK signal pathway in human umbilical vein endothelial cells.

Lu Y ，Zhu X ，Liang GX ，Cui RR ，Liu Y ，Wu SS ，Liang QH ，Liu GY ，Jiang Y ，Liao XB ，Xie H ，Zhou HD ，Wu XP ，Yuan LQ ，Liao EY ... -  《-》

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway.

Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 μM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell-monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase β and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff-Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.

Jia Z ，Nallasamy P ，Liu D ，Shah H ，Li JZ ，Chitrakar R ，Si H ，McCormick J ，Zhu H ，Zhen W ，Li Y ... -  《-》

ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are previously found to possess prostaglandin and leukotriene-independent anti-inflammatory effect. The aim of the present study was to investigate the prostaglandin and leukotriene-independent anti-inflammatory effect of an imidazolone COX/5-LOX inhibitor ZLJ-6 and the underlying mechanism. Pretreatment human umbilical vein endothelial cells (HUVECs) with ZLJ-6 (3, 10 and 30 μM) concentration-dependently decreased TNF-α-induced monocyte-endothelial interactions in both static and dynamic conditions whereas no effect was found after pretreatment with the COX-2 inhibitor celecoxib (30 μM), 5-LOX inhibitor zileuton (30 μM) and the combination of them. ZLJ-6 also attenuated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cytoadhesion molecule-1 (VCAM-1) on TNF-α-induced HUVECs. A further analysis indicated that ZLJ-6 attenuated TNF-α-induced nuclear translocation of NF-κB, IκB phosphorylation, IκB kinase β (IKKβ) activity, and subsequent NF-κB-DNA complex formation, suggesting that NF-κB pathway was involved in TNF-α-induced inflammation. However, ZLJ-6 did not affect TNF-α-induced extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 phosphorylation. Taken together, our results indicated that ZLJ-6 potently inhibited TNF-α-induced monocyte-endothelial interactions and adhesion molecule (E-selectin, ICAM-1 and VCAM-1) expression and these effects were mediated by NF-κB signaling pathway rather than its primary pharmacological target COX-2 or 5-LOX.

Chen L ，Zhao Q ，Wang XL ，You R ，Zhang YH ，Ji H ，Lai YS ... -  《-》

Visfatin-induced expression of inflammatory mediators in human endothelial cells through the NF-kappaB pathway.

Lee WJ ，Wu CS ，Lin H ，Lee IT ，Wu CM ，Tseng JJ ，Chou MM ，Sheu WH ... -  《-》