Damage In Human Vascular Endothelial Cells By Tnf-¦Á Protective Effect Of Compound Danshen Active Monomer

The Chinese herb Salvia miltiorrhiza (SM) has been found to have beneficial effects on the circulatory system including the effect of antiatherosclerosis..Adhesion molecules, which play a crucial role in the development of atherogenesis, are produced by endothelial cells following stimulation with various inflammatory cytokines. The current studies examined the effect of a potent water-soluble antioxidant, protocatechuic aldehyde (derived from the Chinese herb, Salvia miltiorrhiza), on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs) stimulated with tumor necrosis factor-a (TNF-a). Protocatechuic aldehyde appeared to specifically downregulate the TNF-α-induced cell surface expression of vascular adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on HUVECs as well as the release of soluble VCAM-1 and ICAM-1 from HUVECs in a dose-response manner at pharmacologically relevant concentrations (0.15-1.35mM). We also observed a dose-dependent lowering of mRNA expression of VCAM-1 and ICAM-1 in the presence of protocatechuic aldehyde. Furthermore, protocatechuic aldehyde (0.15, 0.45 and 1.35mM) notably inhibited TNF-a-induced upregulation of U937 cell adhesion to HUVECs to 83.7%, 60.9% and 40.8%, respectively. A gel shift assay further showed that protocatechuic aldehyde inhibited the TNF-a-activated Nuclear factor-KB (NF-kB) and AP-1 (active protein 1) DNA binding activities in a dose-dependent manner.In the present study, we also investigated the effects of cryptotanshinone (derived from SM) on endothelin-1 (ET-1) expression in HUVECs. The effect of cryptotanshinone on nitric oxide (NO) in HUVECs was also examined. We found that cryptotanshinone inhibited basal and TNF-a stimulated ET-1 secretion in a concentration-dependent manner. Cryptotanshinone also induced a concentration-dependent decrease in ET-1 mRNA expression. Cryptotanshinone increased basal and TNF-a-attenuated NO production in a dose-dependent fashion. Cryptotanshinone induced a concentration-dependent increase in endothelial nitric oxide synthase (eNOS) expression without significantly changing neuronal nitric oxide synthase (nNOS) expression in HUVECs in the presence or absence of TNF-a. Furthermore, decreased ET-1 expression in response to cryptotanshinone was not antagonized by the NOS inhibitor 1-NAME. A gel shift assay further showed that TNF-a-induced NF-kB activity was significantly reduced by cryptotanshinone. These data suggest that cryptotanshinone inhibits ET-1 production, at least in part, through a mechanism that involves NF-kB but not NO production.Plasminogen activator inhibitor type 1 (PAI-1), which plays a role in the development of atherosclerosis, is produced by endothelial cells following stimulation...