Regulation of human endothelial ICAM-1, E-selectin and VCAM-1 by polyunsaturated fatty acids and antioxidants
The 3 PUFA, EPA and DHA, down-regulated human endothelial adhesion molecules in the presence of an inflammatory stimulus, DHA exerted more pronounced effects than EPA. The 6 PUFA, in contrast, exerted limited control over endothelial adhesion molecule expression under the conditions employed in this study. This indicates that the specific structure of the 3 PUFA, possibly combined with their degree of unsaturation, may be critical to their regulation of endothelial function. The antioxidant, quercetin, down-regulated some cytokine-induced endothelial adhesion molecules. In addition, quercetin acted synergistically with EPA and AA to decrease TNF--induced ICAM-1 or E-selectin protein, respectively. This may reflect regulation of eicosanoid production from these PUFA by quercetin, since this antioxidant inhibits enzymes critical to these metabolic pathways (i.e. cyclooxygenase and lipoxygenase). Hence, quercetin may mediate its inhibitory effects independently of its antioxidant properties. In contrast, -tocopheryl acetate up-regulated IL-1-induced E-selectin proteins levels. This antioxidant also, at least partially, blocked most of the inhibitory actions of the PUFA investigated. Recent data in the literature indicate that PUFA may exert their inhibitory effects on endothelial function through their oxidised derivatives. This provides a putative pathway via which -tocopheryl acetate may block the PUFA effects. The strength and type of inflammatory stimulus determined the sensitivity of the activated endothelial cells to each of the agents investigated. Inhibition of leukocyte adhesion to activated HUVEC, in response to EPA, DHA, or AA in the presence of quercetin, demonstrated a direct effect of these combined agents on endothelial function. The individual agents did not significantly reduce leukocyte adhesion.