Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator inhibitor-1 induction.
Heme oxygenase-1 (HO-1) responds to a variety of oxidative stresses. We examined whether HO-1 expression influences pro-thrombotic processes, in which the involvement of oxidative stress has been reported. Since HO-1 knockout mice with a C57/BL6J background were not viable, embryonic cells from HO-1 deficient mice (E11.5) were used. Cell viability, the level of plasminogen activator inhibitor-1 (PAI-1) expression and reactive oxygen species (ROS) generation of HO-1 deficient cells in response to the exposures to hydrogen peroxide and oxidized LDL were compared to those with wild-type cells. We also examined the effects of glutathione (GSH), desferrioxamine (DFO) and diphenyleneiodonium (DPI: an NADPH oxidase inhibitor) as well as of the HO reaction products, bilirubin (BR) and carbon monoxide (CO) on PAI-1 expression and ROS generation. PAI-1 expression and ROS generation were markedly elevated in HO-1 deficient cells compared to wild-type cells. Exposure to oxidized LDL significantly elevated PAI-1 expression and ROS production in HO-1 deficient cells. Interestingly, these increases in HO-1 deficient cells were significantly lowered by BR, CO, GSH and DPI while DFO had little effect. Furthermore, BR and CO were effective to improve viabilities of HO-1 deficient cells. These results suggest that HO-1 may be required to suppress ROS generation and the production of pro-thrombotic molecules such as PAI-1.
Matsumoto
Hayato
H
First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.
Ishikawa
Kazunobu
K
Itabe
Hiroyuki
H
Maruyama
Yukio
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001663:Bilirubin / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009861:Onium Compounds / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D009861:Onium Compounds; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D005978:Glutathione; D003676:Deferoxamine; D001663:Bilirubin