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

Mol Cell Biochem. 2006 Oct;291(1-2):21-8. doi: 10.1007/s11010-006-9190-y. Epub 2006 Apr 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Bilirubin / pharmacology*
  • Carbon Monoxide / pharmacology*
  • Cell Survival / drug effects
  • Deferoxamine / pharmacology
  • Embryo, Mammalian / cytology
  • Fibroblasts / drug effects
  • Glutathione / pharmacology
  • Heme Oxygenase-1 / deficiency
  • Heme Oxygenase-1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Onium Compounds / pharmacology
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Reactive Oxygen Species / metabolism*


  • Antioxidants
  • Onium Compounds
  • Plasminogen Activator Inhibitor 1
  • Reactive Oxygen Species
  • diphenyleneiodonium
  • Carbon Monoxide
  • Heme Oxygenase-1
  • Glutathione
  • Deferoxamine
  • Bilirubin