Vascular Redox Processes

Group Leader: Professor Roland Stocker

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Overview of Research

The "Oxidative Modification Theory of Atherosclerosis" predicts that oxidative modification of low-density lipoprotein (LDL) is an early event in and a cause of atherosclerosis. Indeed, heightened oxidative stress and oxidative modifications to LDL are key features of atherosclerosis and related diseases. However, atherosclerosis-associated oxidative modifications are not specific for, or limited to, LDL. Also, large prospective studies testing the protective role of natural antioxidants such as vitamin E on cardiovascular disease outcome have yielded disappointing results. This questions the relationship of LDL oxidation and atherosclerosis, as well as the role antioxidants may play in these processes. Past work of our group has helped explain why vitamin E fails to provide protection against atherosclerosis. We have also shown that, in contrast to vitamin E, the synthetic antioxidant probucol consistently prevents atherosclerotic vascular diseases in animals. This protection does not depend on inhibition of LDL oxidation in diseased vessels, but instead requires the drug to induce the protein heme oxygenase-1 (HO-1). We have identified the chemical parts of probucol required for its in vivo efficacy and, in conjunction with industry, are aiming at developing some of our patented novel compounds as anti-atherosclerotic drugs.

Our research aims to understanding how redox processes contribute to atherosclerosis, related disorders and diabetes; and how this can be exploited to develop novel therapeutics.

Current Work

1. A major focus of our work is increasing our understanding of HO-1 biology, at the cellular, tissue, and whole body level. Specifically, we wish to elucidate how induction of the enzyme results in so many different biological benefits, including anti-inflammatory activity, increased protection provided to the endothelium against injury and dysfunction, and the control of cell growth. An immerging interest is the role of HO ‑ 1 in the regulation of gene transcription.
2. Another major focus of our work relates to the functions of the enzyme indoleamine 2,3-dioxygenase (IDO), with a particular focus on its role in the control of vascular tone under conditions of inflammation and oxidative stress, including cardiovascular diseases.
3. We have established a Core Facility, i.e., the Oxidative Stress Bioanalytical Facility. We are developing analytical tools to assess the occurrence of oxidative stress in different cellular compartments and quantify their contribution to cellular functions, with a particular focus on superoxide anion and hydrogen peroxide.

Research Approach and Equipment

Our research approach is multidisciplinary, ranging from chemical synthesis to human applications, the latter through collaborations with clinicians different hospitals. We utilize purified enzymes, yeast genetics, mammalian cell culture, blood vessels and other tissue, histology, various animal models of atherosclerotic vascular disease and diabetes, and human tissue. The technologies employed include analytical tools (in biochemistry, chemistry and physics), cell and molecular biological tools, functional studies related to blood vessels, histology and immunohistochemistry, microscopy and state-of-the art imaging, as well as morphometry and whole body metabolic tests.

Recent Milestones and Important Events

1. Discovery of a novel function of heme oxygenase-1 as a regulator of gene transcription
2. Establishing of a Core Facility to assess oxidative stress
3. Discovery of indoleamine 2,3-dioxygenase as a regulator of vascular tone and blood pressure (published in Nature Medicine)
4. Licensed IP related to novel molecules as anti-atherosclerotic agents to pharmaceutical company in the United States.

Current Projects (all suitable for PhD Students)

1. Role of heme oxygenase-1 in vascular repair including neovascularization
2. Understanding how heme oxygenase-1 regulates gene transcription
3. Identification of the principles underlying the regulation of vascular tone by indoleamine 2,3-dioxygenase
4. The link between heme oxygenase-1, mitochondrial function and cellular energy metabolism
5. Contribution of indoleamine 2,3-dioxygenase to the regulation of vascular tone
6. Assessment and quantification of reactive oxygen species in vivo

Group Members

Key Publications

Collinson EJ, Wimmer-Kleikamp S, Gerega SK, Yang YH, Parish CR, Dawes IW, Stocker R. The yeast homolog of heme oxygenase-1 affords cellular antioxidant protection via the transcriptional regulation of known antioxidant genes. J Biol Chem 2011;286:2205

Wang Y, Liu H, McKenzie G, Witting PK, Stasch J-P, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF Jr, Hunt NH, Stocker R. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 2010;16:270-285

Beck K, Wu BJ, Ni J, Santiago F, Malabanan K, Li C, Wang Y, Khachigian L, Stocker R. Interplay between heme oxygenase-1 and the multifunctional transcription factor Yin Yang 1 in the inhibition of intimal hyperplasia. Circ Res 2010;107:1490-1497

Hoehn K, Salmon A, Hohnen-Behrens C, Turner N, Hoy A, Maghzal G, Stocker R, Van Remme NH, Cooney G, Richardson A, James D. Insulin resistance is a cellular antioxidant defence mechanism. Proc Natl Acad Sci USA 2009;109:17787-17792

Maghzal GJ, Leck MC, Cheng Li C, Collinson E, Stocker R. Limited role for the bilirubin-biliverdin redox amplification cycle in cellular antioxidant protection by biliverdin reductase. J Biol Chem 2009;254:29251-29259

Maghzal G, Thomas SR, Hunt NH, Stocker R. Cytochrome b 5, not superoxide anion radical, is the major reductant of indoleamine 2,3 - dioxygenase in human cells. J Biol Chem 2008;283:12014-12025

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

Hunt NH, Stocker R. Heme moves to center stage in cerebral malaria. Nat Med 2007;13:667-669

Wu BJ, Kathir K, Witting PK, Beck K, Choy K, Li C, Croft KD, Mori TA, Tanous D, Adams MR, Lau AK, Stocker R. Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging. J Exp Med 2006;203:1117-1127

Stocker R, Perrella MA. Heme oxygenase ‑ 1: A novel drug target for atherosclerotic diseases? Circulation 2006;114:2178-2189

Rayner BS, Wu BJ, Raftery M, Stocker R, Witting PK. Human S-nitroso-myoglobin is a store of vasoactive nitric oxide. J Biol Chem 2005;280:9985-9993

Witting PK, Wu BJ, Raftery M, Southwell-Keely P, Stocker R. Probucol protects against hypochlorite-induced endothelial dysfunction: identification of a novel pathway of probucol oxidation to a biologically active intermediate. J Biol Chem 2005;280:15612-15618

Deng YM, Wu B, Witting PK, Stocker R. Probucol protects against smooth muscle cell proliferation by up-regulating heme oxygenase-1. Circulation 2004;110:1861-1866

Stocker R, Keaney JF, Jnr. The role of oxidative modifications in atherosclerosis. Physiol Rev 2004;84:1381-1478