Dr Shane Thomas, NHMRC RD Wright Fellow

Research

Currently we focus on two major research areas of relevance to cardiovascular disease:

1. Identification of the redox reactions and cell signaling pathways important for endothelial dysfunction during vascular disease
2. Study of the roles and regulation of indoleamine 2, 3-dioxygenase
   

1. Oxidative stress and Vascular Endothelial Cell Function

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.
  
• 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 tumour 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 in immune and vascular 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.

Current Grants

Current Funding Sources

National Health and Medical Research Council
National Heart Foundation of Australia
UNSW Faculty of Medicine

Selected Publications

Antler E, Thomas SR, Schulz E, Shapiro O, Vita JA, Keaney JF Jr. 2004. Activation of eNOS by the p38 MAP kinase in response to black tea polyphenols. J Biol Chem. 279, 46637-46643

Stocker R, Huang A, Jeranian E, Hou JY, Wu T, Thomas SR, Keaney JF Jr. 2004. Hypochlorous acid impairs endothelial-derived nitric oxide bioactivity through a superoxide-dependent mechanism. Arterioscler Thromb Vasc Biol. 24, 2028-2033.

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.

Kim HS, Skurk C, Thomas SR, Bialik A, Suhara T, Kureishi Y, Birnbaum M, Keaney JF Jr, Walsh K. 2002. Regulation of angiogenesis by glycogen synthase kinase-3beta. J Biol Chem 277:41888-41896.

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.

Terentis AC, Thomas SR, Takikawa O, Littlejohn TK, Truscott RJ, Armstrong RS, Yeh SR, and Stocker R. 2002. The heme environment of recombinant human indoleamine 2, 3-dioxygenase. Structural properties and substrate-ligand interactions. J Biol Chem 277:15788-15794.

Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. 2001. Dietary co-supplementation with vitamin E and coenzyme Q10 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-?-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.

Thomas SR, Stocker R. 1999. Redox reactions related to indoleamine 2, 3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep 4:199-220.

Thomas SR, Mohr D, Stocker R. 1994. Nitric oxide inhibits indoleamine 2, 3-dioxygenase activity in interferon-? primed mononuclear phagocytes. J Biol Chem 269:14457-14464.