Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging.
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.
Wu
Ben J
BJ
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.
Kathir
Krishna
K
Witting
Paul K
PK
Beck
Konstanze
K
Choy
Katherine
K
Li
Cheng
C
Croft
Kevin D
KD
Mori
Trevor A
TA
Tanous
David
D
Adams
Mark R
MR
Lau
Antony K
AK
Stocker
Roland
R
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*
D001057:Apolipoproteins E; D016166:Free Radical Scavengers; D051547:Heme Oxygenase-1; D011341:Probucol