Inhibitory effect of δ-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion

Abstract

We have previously shown that α-tocotrienol (α-T3), a vitamin E analogue and HMG CoA reductase (HMGR) inhibitor, markedly inhibited monocyte-endothelial cell adhesion, a process that was reversed with the addition of mevalonate intermediates involved in protein prenylation. Since δ-T3 and γ-T3 possess greater HMGR inhibition than α-T3, we postulated that these analogues might have a greater effect on protein prenylation, and thus on monocyte adhesion and endothelial adhesion molecule expression in comparison to α-T3. Hence, we pursued to investigate the effect of various analogues of tocotrienol (α, γ, δ) on monocytic cell adhesion and expression of adhesion molecules using a human umbilical vein endothelial cell-line, EA.hy926, as the model system. Relative to α-T3, δ-T3 displayed a more profound inhibitory effect on monocytic cell adherence using a 15 μmol/L concentration within 24 h (δ: 42±5%; α: 26±8% vs. control). This inhibitory action was reversed by co-incubation with farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of monocyte adhesion. To further evaluate the effect of tocotrienols on the vascular endothelium, we measured the surface expression of adhesion molecules. Compared to α-T3, δ-T3 markedly inhibited the expression of VCAM-1 (δ: 57±6%; α: 37±10% vs. control) and E-selection (δ: 36±3%; α: 18±6% vs. control) in TNF-α activated endothelial cells. The above result suggests that δ-T3 is a potent and effective agent for the reduction of cellular adhesion molecule expression and monocytic cell adherence.