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¹ Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia
² Eastern Heart Clinic, Prince of Wales Hospital, Sydney NSW 2031, Australia
³ Department of Medicine, University of Sydney, and Department of Cardiology, Royal Prince Alfred Hospital, Sydney NSW 2050, Australia
⁴ School of Medicine and Pharmacology, Royal Perth Hospital Unit, University of Western Australia, Perth WA 6001, Australia

CORRESPONDENCE Roland Stocker: r.stocker{at}unsw.edu.au

Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E–deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specific effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.

K. Kathir's present address is Vascular Biology Group, ANZAC Research Institute, Concord Hospital, Concord NSW 2139, Australia.

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