on June 16, 2005
Published online before print June 16, 2005, doi: 10.1161/01.ATV.0000174125.89058.b6
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Submitted on January 11, 2005
Accepted on June 3, 2005
Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice
Katherine Choy ;
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.
* To whom correspondence should be addressed. 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.
Key words: antioxidants • atherosclerosis • collagen • free radicals • inflammation
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