20-Hydroxyeicosatetraenoic Acid Stimulates Nuclear Factor-κB Activation and the Production of Inflammatory Cytokines in Human Endothelial Cells

Abstract

Endothelial dysfunction is associated with endothelial cell activation, i.e., up-regulation of surface cell adhesion molecules and the release of proinflammatory cytokines. 20-Hydroxyeicosatetraenoic acid (HETE), a major vasoactive eicosanoid in the microcirculation, has been implicated in the regulation of endothelial cell function through its angiogenic and pro-oxidative properties. We examined the effects of 20-HETE on endothelial cell activation in vitro. Cells transduced with adenovirus containing either CYP4A1 or CYP4A2 produced higher levels of 20-HETE, and they demonstrated increased expression levels of the adhesion molecule intercellular adhesion molecule (ICAM) (4 -7-fold) and the oxidative stress marker 3-nitrotyrosine (2-3-fold) compared with cells transduced with control adenovirus. Treatment of cells with 20-HETE markedly increased levels of prostaglandin (PG) E 2 and 8-epi-isoprostane PGF 2␣ , commonly used markers of activation and oxidative stress, and most prominently, interleukin-8, a potent neutrophil chemotactic factor whose overproduction by the endothelium is a key feature of vascular injury. 20-HETE at nanomolar concentrations increased inhibitor of nuclear factor-B phosphorylation by 2 to 5-fold within 5 min, which was followed with increased nuclear translocation of nuclear factor-B (NF-B). Likewise, 20-HETE activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway by stimulating phosphorylation of ERK1/2. Inhibition of NF-B activation and inhibition of ERK1/2 phosphorylation inhibited 20-HETE-induced ICAM expression. It seems that 20-HETE triggers NF-B and MAPK/ERK activation and that both signaling pathways participate in the cellular mechanisms by which 20-HETE activates vascular endothelial cells.

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

“…Another apoptosis and infl ammatory mechanism for 7KCh that has been studied in macrophages is the translocation and activation of phospholipase A 2 (PLA 2 ) and arachidonic acid release (124)(125)(126)(127)(128). oxLDL and 7KCh have been shown to induce the translocation of PLA 2 to the plasma membrane and to cause the formation of cholesteryl-and oxysteryl-esters (124)(125)(126)(127)(128).…”

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

“…It has been reported that proinflammatory cytokines elevate the protein level of sEH (13). As 20-HETE can induce the expression of cellular adhesion molecules and cytokines (21), the present study hypothesized that 20-HETE-induced inflammation may be the reason for the increased protein level and activity of sEH. By contrast, EETs have important biological effects on anti-hypertension and anti-inflammation.…”

Cytochrome P450 1B1 Is Critical for Neointimal Growth in Wire‐Injured Carotid Artery of Male Mice

“…However, the cross talk between 12/15‐lipoxygenase and cyclooxygenase 2 pathways, where they can activate each other, has been reported in mesangial cells 49. Because AA metabolism via these enzymes is also associated with generation of ROS,50, 51, 52 it is possible that ROS and/or AA metabolites generated via different enzyme systems stimulate neointimal formation caused by vascular injury, by activating ≥1 common signaling pathways, including extracellular signal‐regulated kinase 1/2 and p38 mitogen‐activated protein kinase 53, 54…”