The interaction of advanced glycation end products (AGE) with their cell surface receptors for AGEs (RAGE) has been causally implicated in the pathogenesis of diabetic vascular complications and has been shown to stimulate cell adhesion molecule expression in endothelial cells via induction of reactive oxygen species (ROS). Alternatively, grape seed proanthocyanidin extracts (GSPE), which are naturally occurring polyphenolic compounds, have been reported to possess potent radical scavenging and antioxidant properties and to display significant cardiovascular protective action. In this study, we investigated whether GSPE could inhibit AGE-induced cell adhesion molecule expression through interference with ROS generations in human umbilical vein endothelial cells. AGE-modified bovine serum albumin (AGE-BSA) was prepared by incubating BSA with a high concentration of glucose. Stimulation of cultured human umbilical vein endothelial cells with 200 microg/mL of AGE-BSA significantly enhanced intracellular ROS formation and subsequently upregulated the expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM-1), whereas both unmodified BSA and GSPE alone were without effect. However, preincubation of different concentrations of GSPE markedly downregulated AGE-BSA-induced VCAM-1 expression at the surface protein and mRNA level in a concentration-dependent manner, but the increased ICAM-1 expression was not affected by GSPE treatment. Meanwhile, the inhibition by GSPE of intracellular ROS generation was also observed at defined time periods. These results demonstrate that GSPE can inhibit the enhanced VCAM-1 expression but not ICAM-1 in AGE-exposed endothelial cells by suppressing ROS generation. Hence, GSPE may have therapeutic potential in the prevention and treatment of vascular complications in patients with diabetes.

Although evidence has shown that grape seed proanthocyanidin extracts (GSPE) can selectively inhibit cell adhesion molecule expression induced by advanced glycation end products (AGEs), the underlying molecular mechanism has not been extensively characterized. To study the antiinflammation mechanism of GSPE, we investigated the effect of GSPE on Von Willebrand factor (vWF) content and the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by AGEs and the effect of GSPE on peroxisome proliferators-activated receptor gamma (PPAR gamma) and receptor for AGEs (RAGE) expression in human umbilical vein endothelial cells (HUVEC). HUVEC were preincubated with or without GSPE of different concentrations (10 mg/L, 50 mg/L, and 100 mg/L) for 4 hours before being treated with 200 mg/L AGEs or unmodified bovine serum albumin (BSA) for 24 hours. The expression of RAGE and PPAR gamma was investigated by Western blot. VCAM-1 expression was measured by flow cytometry and vWF content by enzyme-linked immunosorbent assay (ELISA). Results showed that GSPE significantly inhibited the expression of VCAM-1 in HUVEC and reduced the content of vWF in culture fluid induced by AGEs in a dose-dependent manner. AGEs activated the expression of RAGE and inhibited PPAR gamma expression in HUVEC, whereas GSPE inhibited the expression of RAGE through activation of PPAR gamma in HUVEC simultaneously. These findings indicated that GSPE inhibited the cell inflammatory factor expression and protected the function of endothelial cell through activation of PPAR gamma expression and inhibition of RAGE expression.