YS 51,1-(β-naphtylmethyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline, protects endothelial cells against hydrogen peroxide-induced injury via carbon monoxide derived from heme oxygenase-1

Oxidative stress plays an important role in the pathophysiology of several vascular diseases such as atherosclerosis, and great attention has been placed on the protective role of heme oxygenase-1 (HO-1) for vasculature against oxidant-induced injury. We tested whether the protective effects of YS 51, 1-(P-naphtyl-methyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline, against hydrogen peroxide (H2O2)-induced cell injury is associated with HO-1 activity in bovine aortic endothelial cells (BAEC). YS 51 increased HO-1 expression and activity in concentration-dependent manners (10-100 mu M) and time-dependent manners (1, 3,6,18 h), which were correlated well with its protective effect against H2O2-induced injury. Zinc protoporphyrin IX (ZnPP IX), a HO inhibitor, significantly inhibited the effect of YS 51 (50 mu M). In contrast, [Ru(CO)(3)(Cl)(2)](2) (CORM-2, a CO releasing molecule) but not bilirubin protected against H2O2-induced injury. Oxyhemoglobin (HbO(2)) used as a CO scavenger significantly inhibited the protective effect of both YS 51 and CORM-2. Furthermore, both YS 51 and CORM-2 significantly reduced H2O2-induced intracellular reactive oxygen species (ROS) production; however, this was counteracted by ZnPP IX, HbO(2) and deferoxamine. We found evidence for the involvement of PI3/Akt kinase and ERK1/2 pathways in HO-1 induction by YS-51. Taken together, we conclude that CO is, at least, responsible for the YS SI-mediated protective action of endothelial cells against oxidant stress via HO-1 gene induction, involving the activation of the P13/Akt and ERK1/2 kinase pathways. Thus, YS 51 may be useful in oxidative stress-induced vascular disorders. (C) 2007 Published by Elsevier Inc.