YS 51, 1-(beta-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-(beta-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 microM) 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 microM). In contrast, [Ru(CO)3(Cl)2]2 (CORM-2, a CO releasing molecule) but not bilirubin protected against H2O2-induced injury. Oxyhemoglobin (HbO2) 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, HbO2 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 51-mediated protective action of endothelial cells against oxidant stress via HO-1 gene induction, involving the activation of the PI3/Akt and ERK1/2 kinase pathways. Thus, YS 51 may be useful in oxidative stress-induced vascular disorders.
Heo
Ja Myung
JM
Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, 92 Chilam-dong, Jinju 660-751, South Korea.
Kim
Hye Jung
HJ
Ha
Yu Mi
YM
Park
Min Kyu
MK
Kang
Young Jin
YJ
Lee
Young Soo
YS
Seo
Han Geuk
HG
Lee
Jae Heun
JH
Yun-Choi
Hye Sook
HS
Chang
Ki Churl
KC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
C495109:1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline; D000975:Antioxidants; D017382:Reactive Oxygen Species; D044005:Tetrahydroisoquinolines; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1