Redox Cell Signalling

Group Leader: Dr Shane Thomas

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Overview of Research

The Redox Cell Signalling Laboratory focuses on two major research areas:

1. Identification of the redox reactions and cell signaling pathways important for endothelial dysfunction during vascular disease

The endothelium is critical for the maintenance of vascular homeostasis. Central to this is endothelium-derived nitric oxide (EDNO), synthesized by the endothelial nitric oxide synthase (eNOS). Vascular diseases including diabetes, atherosclerosis and hypertension are characterized by endothelial dysfunction that is manifested as impaired EDNO bioactivity that contributes to clinical cardiovascular events. Considerable evidence shows that endothelial dysfunction is due to oxidative stress in the blood vessel wall and there is great interest in defining the oxidative processes and cell signalling events involved.

Oxidative stress and endothelial dysfunction
This project aims to define the oxidative reactions promoting endothelial dysfunction during vascular disease. At present we focus on the oxidative enzyme myeloperoxidase (MPO) that during vascular disease accumulates in the sub-endothelium of diseased blood vessels where it is ideally placed to impact on endothelial function. We are currently investigating the oxidative and cell signalling mechanisms by which MPO impacts on EDNO bioactivity and endothelial function in vascular disease and testing novel agents for their ability to selectively remove MPO from the endothelium. These agents may represent potential therapeutics to combat endothelial dysfunction.

Redox control of endothelial cell signalling
Reduction and oxidation (redox) reactions represent important transducers of vascular cell signalling pathways. This project aims to identify the redox responsive cell signalling pathways in endothelial cells stimulated with agonists (e.g., vascular endothelial growth factor, angiotensin II) and to define the nature and intracellular source of the redox-active signalling species.

2. Roles and Regulation of Indoleamine 2, 3-Dioxygenase

Indoleamine 2, 3-dioxygenase (IDO) is an intracellular heme enzyme that catalyses the catabolism of L-tryptophan (L-Trp). IDO represents a central immune regulatory enzyme. Thus, expression of IDO in professional antigen presenting cells or tumor cells and resultant depletion of L-Trp, the least abundant essential amino acid, inhibits T lymphocyte activation to promote immune suppression and tolerance during inflammation, transplantation, auto-immunity and cancer.

IDO and Vascular Disease
Atherosclerosis is a chronic inflammatory disease of the artery in which T lymphocyte-mediated immune reactions play an important role. We have detected increased IDO expression in atherosclerotic lesions and currently testing if IDO activity expressed in immune cells inhibits atherosclerosis by limiting T cell activation and vascular inflammation.

Regulation of IDO activity
In light of the important immune regulatory roles of IDO it is important to understand how the enzyme is controlled. Our previous studies were the first to describe post-translational regulation of IDO and this project aims to characterize the post-translational modifications involved and the extent to which they govern the immune regulatory actions of antigen presenting cells and tumour cells. Identification of how IDO is regulated may facilitate the development of novel drug strategies to modulate IDO activity in vivo.

Group Members

Key Publications

Thomas SR†, Witting PK, Drummond GR. 2008 Comprehensive Invited Review - Redox Control of Endothelial Function and Dysfunction: Molecular Mechanisms and Therapeutic Opportunities Antiox Redox Signal. (In Press) †Corresponding Author

King NJ and Thomas SR. 2007 Molecules in Focus: Indoleamine 2,3-dioxygenase. International Journal of Biochemistry & Cell Biology, 39: 2167-2172

Thomas SR†, Terentis AC, Cai H, Takikawa O, Levina A, Lay PA, Freewan M, Stocker R. 2007 Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. J. Biol. Chem. 282: 23778-23787 †Corresponding Author

Thomas SR†, Schulz E, Keaney JF Jr. 2006 Hydrogen peroxide impairs endothelial nitric oxide bioactivity - Role for iron-dependant oxidative stress. Free Radic Biol Med. 41: 681-688 †Corresponding Author

Chen K*, Thomas SR*, Albano A, Murphy MP, Keaney JF Jr., 2004. Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling. J Biol Chem. 279, 35079-35086. (* Co-First Authors)

Chen K, Thomas SR, Keaney JF Jr. 2003. Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic Biol Med 35:117-132.

Thomas SR, Chen K, Keaney JF Jr. 2003. Oxidative stress and endothelial nitric oxide bioactivity. Antioxid Redox Signal 5:181-194.

Thomas SR, Chen K, Keaney JF Jr. 2002. Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and de-phosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. J Biol Chem 277:6017-6024.

Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. 2001. Dietary co-supplementation with vitamin E and coenzyme Q 10 inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol 21:585-593.

Thomas SR, Salahifar H, Mashima R, Hunt NH, Richardson DR, Stocker R. 2001. Antioxidants inhibit indoleamine 2, 3-dioxygenase in IFN-g-activated human macrophages: posttranslational regulation by pyrrolidine dithiocarbamate. J Immunol 166:6332-6340.

Thomas SR, Stocker R. 2000. Molecular action of vitamin E in lipoprotein oxidation: implications for atherosclerosis. Free Radic Biol Med 28:1795-1805.

Funding Sources