{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T13:53:57Z","timestamp":1776347637082,"version":"3.51.2"},"reference-count":65,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,4,17]]},"abstract":"<jats:p>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\u2013deficient 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.<\/jats:p>","DOI":"10.1084\/jem.20052321","type":"journal-article","created":{"date-parts":[[2006,4,10]],"date-time":"2006-04-10T20:33:39Z","timestamp":1144701219000},"page":"1117-1127","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging"],"prefix":"10.1084","volume":"203","author":[{"given":"Ben J.","family":"Wu","sequence":"first","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishna","family":"Kathir","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"},{"name":"2Eastern Heart Clinic, Prince of Wales Hospital, Sydney NSW 2031, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul K.","family":"Witting","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstanze","family":"Beck","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Choy","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Li","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin D.","family":"Croft","sequence":"additional","affiliation":[{"name":"4School of Medicine and Pharmacology, Royal Perth Hospital Unit, University of Western Australia, Perth WA 6001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trevor A.","family":"Mori","sequence":"additional","affiliation":[{"name":"4School of Medicine and Pharmacology, Royal Perth Hospital Unit, University of Western Australia, Perth WA 6001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Tanous","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Adams","sequence":"additional","affiliation":[{"name":"3Department of Medicine, University of Sydney, and Department of Cardiology, Royal Prince Alfred Hospital, Sydney NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony K.","family":"Lau","sequence":"additional","affiliation":[{"name":"2Eastern Heart Clinic, Prince of Wales Hospital, Sydney NSW 2031, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Stocker","sequence":"additional","affiliation":[{"name":"1Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2006,4,10]]},"reference":[{"key":"2023072513412810900_BIB1","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1056\/NEJM198904063201407","volume":"320","year":"1989","journal-title":"N. 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