Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator inhibitor-1 induction

• DOI: 10.1007/s11010-006-9190-y
• Publication Date: 2006-04-19T14:16:30Z
• Authors: Hayato Matsumoto; Kazunobu Ishikawa; Hiroyuki Itabe; Yukio Maruyama
• Keywords: Mice, Knockout; Carbon Monoxide; 0303 health sciences; Cell Survival; Bilirubin; Deferoxamine; Fibroblasts; Embryo, Mammalian; Glutathione; Antioxidants; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Onium Compounds; Plasminogen Activator Inhibitor 1; Animals; Reactive Oxygen Species; Heme Oxygenase-1

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.