Dietary flavonoid apigenin inhibits high glucose and tumor necrosis factor alpha-induced adhesion molecule expression in human endothelial cells

Abstract

Diabetes mellitus is associated with increased endothelial dysfunction and development of atherosclerotic vascular diseases. In contrast, an increased intake of dietary flavonoids is associated with a decreased risk of cardiovascular diseases. Here we demonstrate that high glucose (HG) and tumor necrosis factor alpha (TNFalpha) result in the expression of adhesion molecules and junctional molecules on endothelial cells (EC) within a short time. Simultaneously, we examined the regulatory effects of several dietary flavonoids. We demonstrated the short-term expression of adhesion molecules in a human EC line cultured with normal glucose (5.5 mM), HG (30 mM) and TNFalpha (10 ng/ml) by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry and adhesion assay. The expression of intercellular adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) increased, but that of occludin decreased. Apigenin strongly inhibited the expression of VCAM1, IkappaB kinase (IKK) alpha and IKKepsilon/IKKi, and suppressed the adhesion of U937 cells. From the structure and inhibitory activity of several dietary flavonoids, it was recognized that a double bond between apigenin and the third hydroxyl group was required for inhibition of gene expression. HG and TNFalpha induced the expression of cell adhesion molecules and reduced that of occludin in EC. These flavonoids modified the expression of cloudin 5 and occludin. These results demonstrated that apigenin inhibits HG- and TNFalpha-induced adhesion molecule expression and that flavonoids regulate the expression of junctional molecules in human EC. It is suggested that apigenin inhibited the expression of several genes through inhibition of IKKs.