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

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Abstract

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.

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Abbreviations

C57/BL6J, B6; DCFDA:

chloromethyl-2, 7-dichlorofluorescein diacetate

DFO:

desferrioxamine

DMEM:

Dulbecco's modified Eagle's medium

DPI:

diphenylene iodinium

GSH:

glutathione

HO:

heme oxygenase

LDL:

low density lipoprotein

MCP-1:

monocyte chemotactic protein-1

oxLDL:

oxidized LDL

PAI-1:

plasminogen activator inhibitor-1

PCR:

polymerase chain reaction

ROS:

reactive oxygen species

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Correspondence to Kazunobu Ishikawa.

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Matsumoto, H., Ishikawa, K., Itabe, H. et al. Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator inhibitor-1 induction. Mol Cell Biochem 291, 21–28 (2006). https://doi.org/10.1007/s11010-006-9190-y

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  • DOI: https://doi.org/10.1007/s11010-006-9190-y

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