Thioredoxin and Thioredoxin Reductase Control Tissue Factor Activity by Thiol Redox-dependent Mechanism

Abstract

Background: Oxidant-induced elevation in tissue factor activity increases thrombosis risk. Results: Tissue factor can form a disulfide bridge with human cytosolic thioredoxin and be reduced by thioredoxin-thioredoxin reductase-NADPH along with a decrease in its activity. Conclusion: Thioredoxin/thioredoxin reductase is involved in orchestration of tissue factor-dependent events. Significance: Revealing novel modulators can be exploited for therapeutic benefits in tissue factor-related disorders.

The lipid peroxidation product 4-hydroxy-2-nonenal induces tissue factor decryption via ROS generation and the thioredoxin system

“…Recent studies by Wang et al 17 showed that TrxR/Trx negatively regulates TF coagulant activity in MDA-231 breast cancer cells. HNE was shown to irreversibly inhibit TrxR and Trx activity via modification of their catalytic active residues.…”

“…A recent study by Wang et al 17 showed that the TrxR/Trx system functions as a negative regulator of cell surface TF activity, as Trx knockdown resulted in a significant increase in cell surface TF procoagulant activity in cancer cells. Using purified recombinant soluble TF and Trx, the study showed that the TrxR/Trx redox system reduces the Cys186-Cys209 disulfide bond in TF (Trx forms mixed disulfide bonds with TF) and abrogated TF procoagulant activity.…”

“…Based on this, Wang et al 17 suggested that TrxR/Trx may regulate TF activity at the cell surface through regulation of Cys redox states in the TF extracellular domain. It is also possible that TrxR may also modulate redox states in TF via PDI, because PDI is one of the potential substrates of TrxR.…”

“…[10][11][12] Recent studies suggest that thiol exchange pathways involving protein disulfide isomerase (PDI) regulate TF activation via reversible disulfide bond formation. [13][14][15][16] Wang et al 17 showed that thioredoxin (Trx) knockdown caused a significant increase in cell surface TF procoagulant activity in MDA-MB-231 cells, indicating that the thioredoxin reductase (TrxR)/Trx system negatively regulates TF coagulant activity. Rothmeier et al 18 reported that adenosine triphosphate (ATP)-induced TF activation and TF 1 microvesicle (MV) release in mouse macrophages is also dependent on the TrxR/Trx system.…”

“…Although the mechanism by which the TrxR/Trx system regulates cell surface TF activity is unclear, it had been suggested that PDI-mediated disulfide bond formation in TF may be responsible for TF activation. 17,18 HNE was shown to inhibit Trx either directly by forming a covalent adduct with Trx or indirectly through the inhibition of TrxR activity. 19 These observations raise the possibility that HNE-induced inhibition of TrxR/Trxdependent thiol exchange pathways may be responsible for TF activation in monocytes and macrophages.…”