Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging

• Published in: The Journal of experimental medicine Vol. 203; no. 4; pp. 1117 - 1127
• Main Authors: Wu, Ben J, Kathir, Krishna, Witting, Paul K, Beck, Konstanze, Choy, Katherine, Li, Cheng, Croft, Kevin D, Mori, Trevor A, Tanous, David, Adams, Mark R, Lau, Antony K, Stocker, Roland
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 17.04.2006
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - prevention & control; Coronary Restenosis - enzymology; Coronary Restenosis - genetics; Coronary Restenosis - prevention & control; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - prevention & control; Free Radical Scavengers - administration & dosage; Heme Oxygenase-1 - metabolism; Male; Mice; Mice, Knockout; Probucol - administration & dosage; Rabbits; Rats; Rats, Zucker; Signal Transduction - genetics; Signal Transduction - physiology
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20052321

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.