title: Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Wu
authors.forename: Krishna
authors.initials: K
authors.lastname: Kathir
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Konstanze
authors.initials: K
authors.lastname: Beck
authors.forename: Katherine
authors.initials: K
authors.lastname: Choy
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Mori
authors.forename: David
authors.initials: D
authors.lastname: Tanous
authors.forename: Mark R
authors.initials: MR
authors.lastname: Adams
authors.forename: Antony K
authors.initials: AK
authors.lastname: Lau
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D023903:Coronary Restenosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011341:Probucol / Q000008:administration & dosage*; D011817:Rabbits; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D016166:Free Radical Scavengers; D051547:Heme Oxygenase-1; D011341:Probucol