The epoxyeicosatrienoic acids (EETs), derived from cytochrome P450 epoxygenases, exhibit anti-inflammatory properties in vascular endothelial cells. CYP2J2, a cytochrome P450 isoform, was identified as a key enzyme in human endothelial cells that produces EETs. Physiological concentrations of EETs or overexpression of CYP2J2 reduced cytokine-induced adhesion molecule expression, such as vascular cell adhesion molecule-1 (VCAM-1), by inhibiting the transcription factor NF-κB and its kinase, IκB kinase. This effect was independent of EETs' membrane-hyperpolarizing properties, suggesting a non-vasodilatory role in vascular inflammation. EETs are metabolites of arachidonic acid and include various biologically active eicosanoids. They can hyperpolarize and relax vascular smooth muscle cells by activating calcium-sensitive potassium channels. However, their primary role in vascular inflammation involves inhibiting NF-κB-mediated VCAM-1 expression. CYP2J2 was localized in human coronary artery endothelium and vascular smooth muscle cells, but not in surrounding connective tissue. Other cytochrome P450 epoxygenases, such as CYP1A, CYP2C8, and CYP2B1, were also identified in endothelial cells, but their functional role in the human coronary artery remains unclear. Using transfected bovine aortic endothelial cells, EET synthesis was measured, showing that CYP2J2-transfected cells produced EETs at a higher rate than control cells. The anti-inflammatory effects of EETs were tested in cytokine-activated human endothelial cells, where [11,12]-EET significantly inhibited TNF-α-induced VCAM-1 expression. This effect was not blocked by selective KCa channel blockers, indicating that the mechanism is independent of EETs' hyperpolarizing effects. [11,12]-EET also inhibited expression of other adhesion molecules, such as ICAM-1 and E-selectin. The inhibitory effect of [11,12]-EET on VCAM-1 expression was mediated by the repression of κB cis-acting elements in the VCAM-1 promoter. This was confirmed by transient transfection experiments and by showing that [11,12]-EET reduced TNF-α-induced VCAM-1 and κB promoter activity. The effect was reversed by the cytochrome P450 epoxygenase inhibitor SKF-525A. In addition, [11,12]-EET inhibited TNF-α-induced VCAM-1 expression by preventing the nuclear translocation of NF-κB subunit Rel A, which requires the degradation of its inhibitor, IThe epoxyeicosatrienoic acids (EETs), derived from cytochrome P450 epoxygenases, exhibit anti-inflammatory properties in vascular endothelial cells. CYP2J2, a cytochrome P450 isoform, was identified as a key enzyme in human endothelial cells that produces EETs. Physiological concentrations of EETs or overexpression of CYP2J2 reduced cytokine-induced adhesion molecule expression, such as vascular cell adhesion molecule-1 (VCAM-1), by inhibiting the transcription factor NF-κB and its kinase, IκB kinase. This effect was independent of EETs' membrane-hyperpolarizing properties, suggesting a non-vasodilatory role in vascular inflammation. EETs are metabolites of arachidonic acid and include various biologically active eicosanoids. They can hyperpolarize and relax vascular smooth muscle cells by activating calcium-sensitive potassium channels. However, their primary role in vascular inflammation involves inhibiting NF-κB-mediated VCAM-1 expression. CYP2J2 was localized in human coronary artery endothelium and vascular smooth muscle cells, but not in surrounding connective tissue. Other cytochrome P450 epoxygenases, such as CYP1A, CYP2C8, and CYP2B1, were also identified in endothelial cells, but their functional role in the human coronary artery remains unclear. Using transfected bovine aortic endothelial cells, EET synthesis was measured, showing that CYP2J2-transfected cells produced EETs at a higher rate than control cells. The anti-inflammatory effects of EETs were tested in cytokine-activated human endothelial cells, where [11,12]-EET significantly inhibited TNF-α-induced VCAM-1 expression. This effect was not blocked by selective KCa channel blockers, indicating that the mechanism is independent of EETs' hyperpolarizing effects. [11,12]-EET also inhibited expression of other adhesion molecules, such as ICAM-1 and E-selectin. The inhibitory effect of [11,12]-EET on VCAM-1 expression was mediated by the repression of κB cis-acting elements in the VCAM-1 promoter. This was confirmed by transient transfection experiments and by showing that [11,12]-EET reduced TNF-α-induced VCAM-1 and κB promoter activity. The effect was reversed by the cytochrome P450 epoxygenase inhibitor SKF-525A. In addition, [11,12]-EET inhibited TNF-α-induced VCAM-1 expression by preventing the nuclear translocation of NF-κB subunit Rel A, which requires the degradation of its inhibitor, I