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Group Leader: Roland Stocker Overview: Roland's group is the "Vascular Redox Processes Group". Heightened oxidative stress is a key feature of atherosclerosis and related diseases, although it remains to be elucidated how precisely they impact on disease progression and how compounds that counteract oxidation reactions may attenuate disease. Roland's team has shown that probucol, a lipid-lowering drug with antioxidant properties, prevents atherosclerosis and restenosis in animal models. Surprisingly, this protective activity is unrelated to the inhibition of lipoprotein oxidation in the diseased vessel wall but instead appears to be linked to beneficial effects on cellular functions. Roland's research aims are to characterize these beneficial cellular activities of probucol as well as probucol analogues that the group has patented and that show in vivo activity. The overall aim is to develop drugs effective as anti-restenotic drugs. 
Re-endothelialization promoting activity
of probucol
Projects: Atherosclerosis
Atherosclerosis is the major underlying cause of cardiovascular diseases, and prevention of the early stages of atherosclerosis is a major target for drug development. Roland's team has shown that certain types of antioxidants inhibit atherosclerosis in different animal models of the disease. The research focus now is to characterize the protective activities of these antioxidants in vivo. A separate project aims at establishing a novel, non-invasive diagnostic that allows determination of the extent of atherosclerotic disease in individuals. The project is based on specific protein modifications and their detection in circulation during atherosclerosis. Restenosis
Restenosis after angioplasty remains a significant problem of current interventional cardiology. Roland's team has shown that compounds that promote the process of re-endothelialization after vascular injury inhibit restenosis in animal models. The research focus now is to elucidate the molecular mechanism underlying this beneficial activity, and to extend our studies to in-stent restenosis. Control of Vascular Tone
The maintenance of vascular homeostasis plays a central role in the prevention of vascular diseases, and dilation of vessel wall in response to various stimuli is a key component of vascular homeostasis. Roland's group has identified a potential novel endogenous pathway that contributes to the control of vascular tone. The team is now characterizing this novel pathway and mode of action of its active component.
Group members:
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Key Publications: Choy K, Beck K, Png FY, Leichtweis SB, Wu BJ, Thomas SR, Hou JY, Croft KD, Mori TA, Stocker R. Processes involved in the site-specific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice. Arterioscl Thromb Vasc Biol 2005;25:1684-1690
Lau AK, Chafour X, McLachlan C, Leichtweis, Steven B, Celermajer DS, Sullivan C, Stocker R. Intimal thickening after arterial balloon injury is increased by repetitive hypoxia but repetitive hyperoxia is not protective. Atherosclerosis 2005;in press
Stocker R, Pollicino C, Gay CA, Nestel P, Colquhoun D, Whiting M, Tonkin A, Sullivan D, Simes J. Neither plasma coenzyme Q10 concentration, nor its decline during statin therapy, is linked to recurrent cardiovascular disease events: A prospective case-control study from the LIPID study. Atherosclerosis 2005;in press
Parker G, Heruc GA, Hilton TM, Olley A, Brotchie H, Hadzi-Pavlovic D, Friend C, Walsh WF, Stocker R. Low levels of docosahexaenoic acid in depressed patients with coronary artery disease. Psychiatry Research 2005;in press 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(IF=6.5)
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(IF=6.5) Dallner G, Stocker R.
Coenzyme Q10. In Encyclopedia of Dietary Supplements. Eds. Coates P, Blackman MR, Cragg G, Levine M, Moss J, White P (Marcel Dekker, New York) 2005;121-131 Yamauchi R, Southwell-Keely P, Suarna C, Ray S, Raftery M, Cynshi O, Stocker R.
Characterization of the oxidation products of BO-653 formed during peroxyl radical-mediated oxidation of human plasma. Free Radic Biol Med 2005;38:32-40. (IF=5.1) Panzenböck U, Stocker R.
Formation of methionine sulfoxide-containing specific forms of oxidized high-density lipoproteins. Biochim Biophys Acta 2005;1703:171-181 (IF=2.8)
Stocker R, Keaney JF, Jr.
Chapter 5: Oxidative stress and atherosclerosis. In Molecular mechanisms of atherosclerosis. Ed. Loscalzo J (Taylor & Francis, Lancaster) 2005;61-83 Rayner BS, Stocker R, Lay PA, Witting PK.
Regio- and stereo-chemical oxidation of linoleic acid by human myoglobin and hydrogen peroxide. Tyrosine residue 103 affects rate and product distribution. Biochem J 2004;81:365-372. Aitken JB, Thomas SE, Stocker R, Thomas SR, Takikawa, O, Armstrong RS, Lay PA. Determination of the nature of the heme environment in nitrosyl indoleamine 2,3-dioxygenase using multiple-scattering analyses of XAFS. Biochemistry 2004,43:4892-4898.
Stocker R, Huang A, Jeranian E, Hou JY, Wu T, Thomas SR, Keaney JF, Jr.
Hypochlorous acid impairs EDNO bioactivity through a superoxide-dependent mechanism. Arterioscl Thromb Vasc Biol 2004; in press. Stocker R, Keaney JF, Jnr.
The role of oxidative modifications in atherosclerosis. Physiol Rev 2004;84:1381-1478. Kontush A, Chapman MJ, Stocker R.
Vitamin E is not deficient in human atherosclerotic plaques. Arterioscl Thromb Vasc Biol 2004;24:e139-e140. Stocker R, Huang A, Jeranian E, Hou JY, Wu T, Thomas SR, Keaney JF, Jr.
Hypochlorous acid impairs EDNO bioactivity through a superoxide-dependent mechanism. Arterioscl Thromb Vasc Biol 2004;24:2028-2033. Rayner BS, Wu BJ, Raftery M, Stocker R, Witting PK.
Regulation of vascular tone by S-nitroso-myoglobin. Redox Report 2004;9:382-386 (IF=1.6) Lau A, Hume P, Mashima R, Hou JY, Chaufour X, Wilkinson B, Hunt NH, Celermajer DS Stocker R.
Probucol promotes functional re-endothelialzation in balloon-injured rabbit aortas. Circulation 2003;107:2031-2036 Upston JM, Niu X, Brown AJ, Mashima R, Wang H, Senthilmohan R, Kettle AJ, Dean RT, and Stocker R.
Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis. Am J Pathol 2002;160:701-710. Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R.
Vitamin E oxidation in human atherosclerotic lesions. Circ Res 2002;90:333-339. Thomas SR, Salahifar H, Mashima R, Hunt NH, Richardson D, Stocker R.
Antioxidants inhibit indoleamine 2,3-dioxygenase in interferon?-activated human macrophages. Post-translational regulation by pyrrolidine dithiocarbamate. J Immunol 2001;166:6332-6340. Oram JF, Vaughan A, Stocker R.
ATP-binding cassette transporter A1 mediates cellular secretion of alpha?tocopherol. J Biol Chem 2001;276:39898-39902. Panzenböck U, Kritharides L, Raftery M, Rye K-A, Stocker R.
Oxidation of methionine residues to methionine sulfoxides enhances rather than decreases potential anti-atherogenic properties of apolipoprotein A-I. J Biol Chem 2000;275:19536-19544. Witting PK, Pettersson K, Letters J, Stocker R.Site-specific anti-atherogenic effect of probucol in apolipoprotein E deficient mice. Arterioscl Thromb Vasc Biol 2000;20:e26-e33. Witting PK, Pettersson K, Lindqvist A-M, Westerlund C, Westin Eriksson A, Stocker R.
Inhibition by a co-antioxidant of aortic lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice. FASEB J 1999;13:667-675. Stocker R.The ambivalence of vitamin E in atherogenesis. Trends in Biological Sciences 1999;24:219-223. 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. References from Shane Thomas: Anter E, Thomas SR, Schulz E, Shapira OM, Vita JA, Keaney JF Jr. Activation of endothelial nitric-oxide synthase by the p38 MAPK in response to black tea polyphenols.
J Biol Chem. 2004;279:46637-46643
Chen K, Thomas SR, Albano A, Murphy MP, Keaney JF Jr. Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling. J Biol Chem. 2004;279):35079-35086
Heydrick SJ, Weiss N, Thomas SR, Cap AP, Pimentel DR, Loscalzo J, Keaney JF Jr. L-Homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med. 2004;36:632-640
Chen K, Thomas SR, Keaney JF Jr. Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic Biol Med. 2003;35:117-132
Thomas SR, Chen K, Keaney JF Jr. Oxidative stress and endothelial nitric oxide bioactivity. Antioxid Redox Signal. 2003;5:181-194
Huang A, Thomas SR, Keaney JF Jr. Measurements of redox control of nitric oxide bioavailability. Methods Enzymol. 2002;359:209-216
Kim HS, Skurk C, Thomas SR, Bialik A, Suhara T, Kureishi Y, Birnbaum M, Keaney JF Jr, Walsh K. Regulation of angiogenesis by glycogen synthase kinase-3beta. J Biol Chem. 2002;277:41888-41896 Prizes and Awards Josephine May Hammond Research Award, National Heart Foundation.
Heme oxygenase-1 as a general target for pharmacotherapy against atherosclerotic vascular disease
Anthony Mason Fellowship
Grants:
2001-2005: National Health & Medical Research Council of Australia:
Fellowship at Senior Principal Research Fellow
2003-07 National Health & Medical Research Council of Australia: Program Grant: Atherosclerosis, together with Prof. David Celermajer, Prof. Philip Barter, A/Prof. Wendy Jessup, and A/Prof. Kerry-Anne Rye.
2003-07 Australian Research Council: "Cellular responses to oxidative damage: cell aging. Co-investigator together with Prof. IW Dawes (CIA) and Prof. M Breitenbach (CIB)2005-06: Merck Sharp & Dohme, Australia:
Development of small molecules as potential agents for reducing vascular wall inflammation.
($90,000) 2005-06 National Heart Foundation of Australia:
"Control of von Willebrand factor haemostatic activity by myeloperoxidase-derived oxidants" ($117,712); RS co-investigator with Philip Hogg (CIA) 2005-06 National Heart Foundation of Australia:
"Role of indoleamine 2,3-dioxygenase in vascular disease"; RS co-investigator with Shane Thomas (CIA); Application successful, though funding not provided as research falls within that covered by NHMRC Project Grant Application. 2005-06 National Heart Foundation of Australia:
"Heme oxygenase-1 as a general target for therapeutic agents against atherosclerotic vascular disease" ($120,000); RS together with Shane Thomas (Senior Investigator) Shane Thomas: National Health & Medical Research Council of Australia:
Career Development Award (2006-2010) Roland Stocker: National Health & Medical Research Council of Australia:
Senior Principal Research Fellowship (2006-2010)
Roland Stocker: National Health & Medical Research Council of Australia:
Project Grant: “Tryptophan metabolism and vascular tone”; together with Professor NH Hunt (CIB) (2006-2008)
Roland Stocker: National Health & Medical Research Council of Australia:
Equipment Grant: Multi Myograph System 610M; together with M Hill, L Khachigian, L Kritharides (2005) Funding sources: NH&MRC
ARC
National Heart Foundation Roland's team is developing novel compounds that inhibit restenosis. This technology is the subject of existing and pending International and Australian Patent Applications.
Roland's group also has a lead compound for the non-invasive diagnostic of atherosclerosis that is the subject of Patent Applications.
Roland has a long-standing record of commercial funding with major international pharmaceutical companies. At present, his team has several commercial contracts with Chugai Pharmaceuticals Co. Ltd, with whom it is involved in a Phase-II clinical trial related to a novel anti-restenotic drug. Patents: Inventors & Stage: Lindqvist AM, Pettersson K, Stocker R, Westerlund C, Witting PK. United States Patent 6,031,008; Australian Letters Patent 711275; New Zealand Letters Patent 332196; Singapore Patent P-57011; Canada Patent 2251269 Description: A method for detection of potential co-antioxidantsInventors & Stage: Stocker R; National Phase (PCT/AU01/00835); International Patent Application; US Patent Application Description: Compositions and methods for treating cardiovascular disorders Inventors & Stage: Stocker R, Wilcken D, Wang XL; National Phase (PCT/AU00/01463); International Patent Application; US Patent Application Description: Oxidized apolipoproteins and methods of use
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