Processes involved in the site-specific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice.
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.


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 (alpha-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 alpha-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.
Choy
Katherine
K
Centre for Vascular Research, University of New South Wales, Sydney, Australia.
Beck
Konstanze
K
Png
Francoise Y
FY
Wu
Ben J
BJ
Leichtweis
Steven B
SB
Thomas
Shane R
SR
Hou
Jing Y
JY
Croft
Kevin D
KD
Mori
Trevor A
TA
Stocker
Roland
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000187:drug effects; D011341:Probucol / Q000493:pharmacokinetics / Q000494:pharmacology*; D012850:Sinus of Valsalva / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001057:Apolipoproteins E; D011341:Probucol