7,8-didehydrocimigenol from Cimicifugae rhizoma inhibits TNF-alpha-induced VCAM-1 but not ICAM-1 expression through upregulation of PPAR-gamma in human endothelial cells

Abstract

Activators of PPAR have been demonstrated to inhibit the induction of VCAM-1 but not ICAM-1 in human endothelial cells (EC). During the screening of anti-inflammatory activity of traditional herbs, we found 7,8-didehydrocimigenol (7,8-DHC), one of active triterpenoids of Cimicifugae rhizoma (C rhizoma) increases PPAR-gamma expression in EC in a time- and dose-dependent manner. Therefore, we asked whether 7,8-DHC selectively inhibits the expression of VCAM-1 but not ICAM-1 in TNF-alpha-activated EC via upregulation of PPAR-gamma. Treatment with 7,8-DHC or PPAR-gamma agonists (GW1929, troglitazone) inhibited the expression of VCAM-1 but not ICAM-1. Furthermore, the selective inhibition of VCAM-1 expression was inhibited by PPAR-gamma antagonist, GW9662, or siPPAR-gamma-transfected cells. 7,8-DHC significantly inhibited NF-kB activity via inhibition of phosphorylation of IkB and it also inhibited phosphorylation of ERK1/2 and Akt but not PKC. Finally, attachment of monocytes (U937) to EC by TNF-alpha was significantly reduced by 7,8-DHC. These results indicate that upregualtion of PPAR-gamma by 7,8-DHC in EC inhibits NF-kB activity of TNF-alpha-activated EC which leads to selective inhibition of VCAM-1 expression. In addition, ERK1/2 and Akt signal pathways are involved in differential regulation by 7,8-DHC. We concluded that 7,8-DHC can be used for the treatment of cardiovascular disorders such as atherosclerosis. (c) 2010 Elsevier Ltd. All rights reserved.