Vascular
Biology

"To do its job effectively, the heart
needs the blood vessels to be in
good condition too,"

- Professor Roland Stocker 


Professor Roland Stocker

Head, Vascular Biology laboratory

Research Overview

Key Research Areas

  • Atherosclerosis
  • Vascular disease, heart attack and stroke
  • Oxidative stress

Research Overview

Atherosclerosis is the biggest cause of heart attack, stroke and death in Australia.

It occurs when the walls of your arteries, which carry oxygen to your heart, become thick and stiff due to a build-up of fatty deposits. Over time, atherosclerosis causes arteries to become hardened, restricting blood flow to the heart and other organs, which may require intervention.  Some atherosclerotic lesions are vulnerable to ‘rupture’, and this can be fatal.

Professor Roland Stocker and his team are trying to understand what goes wrong in the arteries, how they become diseased and how atherosclerosis can be prevented. More specifically, they examine the contribution of oxidative processes to atherosclerosis and related vascular diseases.

research projects

There are 6 key projects underway in the Vascular Biology Laboratory, led by Professor Roland Stocker;

1. Novel drug candidates to treat vascular dysfunction and stabilize atherosclerotic plaques.

This project addresses the possibility that inhibiting a specific oxidant-producing enzyme, i.e., myeloperoxidase, may stabilize ‘vulnerable’ lesions and hence may prevent a heart attack or stroke. Myeloperoxidase is expressed in certain white blood cells. The enzyme plays an important role in the innate immune system by producing hydrogen peroxide and hypochlorite (bleach) to kill bacteria and other pathogens. However, there is also evidence for myeloperoxidase contributing to the initiating event in atherosclerosis called endothelial dysfunction. In addition, myeloperoxidase has been implicated in plaque rupture. 

The project is a collaboration with Professor Tony Kettle (University of Otago, Christchurch), Professor Karlheinz Peter (Baker IDI, Melbourne) and AstraZeneca. It makes use of a new class of molecules, i.e., 2-thioxanthines, that effectively inhibit myeloperoxidase. We have already shown that 2-thioxanthines rescue endothelial function in animal models of inflammation. We are currently investigating the mechanism by which 2-thioxanthines affect endothelial cell function, atherosclerosis and related processes such as plaque rupture. This is the first time pharmacological inhibition of myeloperoxidase activity is being tested as therapy to stabilize atherosclerotic plaques. If successful, our studies may open the way for the development of a completely novel class of anti-atherosclerotic drugs. 

2. Non-invasive imaging of vulnerable atherosclerotic plaques

Acute myocardial infarction ('heart attack') remains the most common cause of death in Australia and atherosclerotic plaque rupture with blood clotting and artery blockage accounts for the majority of myocardial infarctions. Despite this, assessment of specific characteristics that predispose plaques to rupture is not currently incorporated into standard diagnostic or treatment regimes. Non-invasive, molecular imaging of biological processes known to contribute to plaque rupture is an exciting new way to potentially identify patients at risk of heart attack. As myeloperoxidase has been implicated in plaque rupture, it is an ideal target for molecular imaging. Our laboratory is currently assessing the utility of molecular imaging of myeloperoxidase activity using state-of-the art imaging techniques such as magnetic resonance imaging (MRI) and fluorescence tomography to specifically identify vulnerable plaque in a novel mouse model of plaque rupture. The validation of such diagnostic tools could have significant impact for the assessment management of heart disease.

3. Characterization of a novel pathway that regulates vascular tone in inflammation.

High blood pressure is a major cause for morbidity and mortality in Australia. A key contributor to blood pressure is determined by vascular tone (the level of constriction and relaxation imposed on an artery). We previously reported that, under conditions of inflammation, degradation of the amino acid tryptophan by the enzyme indoleamine 2,3-dioxygenase produces a compound that relaxes arteries and decreases blood pressure. In collaboration with Professor Richard Payne (University of Sydney) we have now discovered a novel compound, derived from the degradation of tryptophan that acts as a vasorelaxant.  The present project will characterize how this compound relaxes blood vessels, and establish under which conditions it is formed in animals and humans. The project is a collaboration with Professor Philip Eaton (King’s College, London), Professor Paolo di Mascio (University of Sao Paolo) and Professor Yorihiro Yamamoto (Tokyo University of Technology).

4. Elucidation of how a heme degrading enzyme protects against vascular hypoxia, atherosclerosis and related diseases.

Heme oxygenase-1 degrades heme to iron, biliverdin and carbon monoxide. The enzyme plays a key role in iron homeostasis and protects against cardiovascular diseases. However, the mechanisms underlying these protective effects are largely unknown. Previous studies have established that heme oxygenase-1 is important for the repair of injured blood vessels, the formation of new blood vessels in response to ischemia (lack of oxygen to tissue), and the inhibition of the uncontrolled growth of vascular smooth muscle cells. Recently we have identified a new role for heme oxygenase-1 in cell metabolism in response to ischemia, and a novel form of heme oxygenase-1 that promotes vascular repair and regeneration. In another study we have commenced testing the possibility that heme oxygenase-1 protects against the development of vulnerable atherosclerotic plaques and plaque rupture. The projects are being carried out in collaboration with Professor Martin Ng (Heart Research Institute, Sydney) and Professor Karlheinz Peter (Baker IDI, Melbourne).

5. Does bilirubin protect against atherosclerosis?

Bilirubin is a product of heme catabolism and formed from biliverdin by biliverdin reductase-a. Bilirubin may protect against atherosclerosis because it has potential protective properties, including antioxidant and anti-inflammatory activities, and the ability to inhibit and promote the growth of vascular smooth muscle and endothelial cells, respectively. Plasma bilirubin concentrations inversely associate with the risk of cardiovascular disease, although a direct link between bilirubin and cardiovascular disease remains to be established, particularly as other products formed during heme degradation, i.e., carbon monoxide, iron and biliverdin could also provide protection. The current project examines the effect of biliverdin reductase-a gene deficiency in experimental models of atherosclerosis and plaque rupture. Ultimately, the project will determine if bilirubin itself is responsible for atheroprotective effects and if protection is due to the antioxidant activity of the pigment.

6. Novel regulatory pathway for the synthesis of the mitochondrial electron transfer agent coenzyme Q

Coenzyme Q is a lipid essential for mitochondrial energy production and normal cell function. Coenzyme Q concentrations are decreased in hearts of heart failure patients and it is hypothesized that coenzyme Q deficiency contributes to heart failure progression. Thus targeting steps regulating Coenzyme Q content may be a novel strategy to increase cellular coenzyme Q concentrations. However, relatively little is known about how cells regulate coenzyme Q concentrations. We recently identified over 100 novel genes from a yeast genome-wide screen that were essential for maintaining cellular coenzyme Q concentrations. The project is currently characterizing these genes in both yeast and mammalian cells to understand how they regulate cellular coenzyme Q concentrations concentrations. By understanding how these genes affect coenzyme Q concentrations content, we hope to identify new pathways and strategies to increase coenzyme Q concentrations content in patients with heart failure. These studies are carried out in collaboration with Professor Ian Dawes (University of New South Wales, Sydney) and Professor Catherine Clarke (University of California, Los Angeles).

Laboratory Members & Collaborators

Laboratory

Anita Ayer, Senior Postdoctoral Scientist

David Cheng, Postdoctoral Scientist

Weiyu Chen, PhD Student

Louise Dunn, Senior Staff Scientist

Stephanie Kong, Postdoctoral Scientist

Kaiming Luo, PhD Student

Ghassan Maghzal, Senior Staff Scientist

Naomi McKinnon, Research Assistant

Darren Newington, Senior Research Assistant

Jessica Phan, Honours Student

Christopher Stanley, Postdoctoral Scientist

Cacang Suarna, Senior Research Assistant

Jihan Talib, Postdoctoral Scientist

Collaborators

Dr James Cantley, University of Oxford

Prof Catherine Clarke, University of California

Prof Kevin Croft, University of Western Australia

Prof Ian Dawes, University of New South Wales

Prof Tony Kettle, University of Otago

A/Prof Martin Ng, Heart Research Institute

Prof Karlheinz Peter, Baker IDI

Prof Yorihiro Yamamoto, Tokyo University of Technology

Prof Philip Eaton, King’s College London

Prof Paolo di Mascio, University of Sao Paolo

Publication Highlights

1. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043-1046

2. Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA 1987;84:5918-5922

3. Frei B, Stocker R, Ames BN. Antioxidant defense and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 1988;85:9748-9752

4. Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does a-tocopherol. Proc Natl Acad Sci USA 1991;88:1646-1650

5. Bowry VW, Stanley KK, Stocker R. High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci USA 1992;89:10316-10320

6. Bowry VW, Stocker R. “Tocopherol mediated Peroxidation”. The prooxidant effect of vitamin E on the radical-mediated oxidation of human low-density lipoprotein. J Am Chem Soc 1993;115:6029-6044

7. Christen S, Thomas SR, Garner, B, Stocker R. Inhibition by interferon-g of mononuclear cell-mediated oxidation of LDL. Participation of tryptophan metabolism along the kynurenine pathway. J Clin Invest 1994;93:2149-2158

8. Hazell LJ, Flowers D, Waeg G, Malle E, Arnold L, Stocker R. Presence of hypochlorite-modified protein in human atherosclerotic lesions. J Clin Invest 1996;97:1535-1544

9. Witting PK, Pettersson K, Östlund-Lindqvist A-M, Westerlund C, Westin Eriksson A, Wågberg M, Stocker R. Dissociation of atherogenesis from aortic accumulation of lipid hydro(pero)xides in Watanabe heritable hyperlipidemic rabbits. J Clin Invest 1999;104:213-220

10. Oram JF, Vaughan A, Stocker R. ATP-binding cassette transporter A1 mediates cellular secretion of a–tocopherol. J Biol Chem 2001;276:39898-39902

11. Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic lesions. Circ Res 2002;90:333-339

12. Lau A, Leichtweis SB, Hume P, Mashima R, Hou JY, Chaufour X, Wilkinson B, Hunt NH, Celermajer DS Stocker R. Probucol promotes functional re-endothelialization in balloon-injured rabbit aortas. Circulation 2003;107:2031-2036

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

14. 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

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

16. 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

17. 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

18. Maghzal GJ, Cergol KM, Shengule SR, Suarna C, Newington D, Kettle AJ, Payne RJ, Stocker R. Assessment of myeloperoxidase activity by the conversion of hydroethidine to 2-chloroethidium. J Biol Chem 2014;289:5580-5595

19. Maghzal GJ, Winter S, Wurzer B, Chong BH, Holmdahl R, Stocker R. Tryptophan catabolism is unaffected in chronic granulomatous disease. Nature 2014;514:E16-E17

20. Ayer A, Zarjou A, Agarwal A, Stocker R. Heme oxygenases in vascular health and disease. Physiol Rev 2016;96:1449-1508

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