Published online before print June 16, 2005, doi: 10.1161/01.ATV.0000174125.89058.b6
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice
From Centre for Vascular Research (K.C., K.B., F.Y.P., B.J.W., S.R.T., R.S.), University of New South Wales, Sydney, Australia; Heart Research Institute (S.B.L., J.Y.H.), Sydney, Australia; University of Western Australia (K.D.C., T.A.M.), School of Medicine and Pharmacology, Perth, Western Australia, Australia.
Correspondence to Prof Roland Stocker, Centre for Vascular Research, School of Medical Sciences, Faculty of Medicine, University of New South Wales, UNSW Sydney, NSW 2052, Australia. E-mail r.stocker{at}unsw.edu.au
Objective— To elucidate processes by which the antioxidant probucol increases lesion size at the aortic sinus and decreases atherosclerosis at more distal sites in apolipoprotein E–deficient (apoE–/–) mice.
Methods and Results— Male apoE–/– mice were fed high-fat chow with 1% (w/w) probucol or without (controls) for 6 months, before aortic sinus, arch, and descending aorta were analyzed separately for lesion size and composition. Compared with control, probucol significantly increased lesion size by 33% at the sinus, but it inhibited atherosclerosis at the descending aorta by 94%. Sites where atherosclerosis was inhibited contained substantially fewer macrophages, less lipids (cholesterol and cholesteryl esters), and endogenous antioxidant (
-tocopherol), but not oxidized lipids, and the extent to which probucol metabolism occurred was increased. Compared with control, aortic sinus lesions of probucol mice contained a substantially increased content of extracellular matrix, but decreased total cell and macrophage density, comparable levels of lipids and -tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F2-isoprostanes, and 7-ketocholesterol).
Conclusions— Probucol affects atherosclerosis in apoE–/– mice independent of the accumulation of arterial lipid oxidation products, thereby dissociating the 2 processes. Rather, probucol exerts antiinflammatory activity by decreasing accumulation of macrophages in lesions, and it promotes a more stable lesion composition at the aortic sinus.
We investigated how the antioxidant probucol increases lesion size at the sinus and decreases atherosclerosis at distal sites in apolipoprotein E-deficient mice. Probucol affected atherosclerosis independent of arterial lipid oxidation. Rather, probucol decreased accumulation of macrophages in lesions, and it promoted a more stable lesion composition at the aortic sinus.
Key Words: antioxidants • atherosclerosis • collagen • free radicals • inflammation
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