Prevention of atherosclerotic progression in Watanabe rabbits by probucol.
The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons, and also of atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore macrophages may be the progenitor of certain foam cells that are involved in atherogenesis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of certain chemically modified lipoproteins, such as acetylated low-density lipoprotein (LDL) and malondialdehyde-treated LDL, through the process of receptor-mediated endocytosis. By this process, macrophages become foam cells. But this process has not been demonstrated in vivo. Recently, oxidized LDL has been suggested to play an important role in atherogenesis by facilitating the accumulation of lipids in macrophages in vitro. Probucol, originally developed as an antioxidant, prevents this oxidative modification of LDL in vitro. Moreover, there are some clinical reports that probucol induces regression of cutaneous and tendon xanthomas in patients with homozygous familial hypercholesterolemia. A question was posed whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At age 2 months, 8 WHHL rabbits were classified into 2 groups: group A rabbits were controls and group B rabbits were treated with 1% probucol. After 6 months of treatment, average plasma concentrations of cholesterol were 704 +/- 121 mg/dl in group A and 584 +/- 61 mg/dl in group B. The percentage of surface area of total thoracic aorta with visible plaques in group A vs group B was 54.2 +/- 18.8% vs 7.0 +/- 6.3%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Kita
T
T
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Nagano
Y
Y
Yokode
M
M
Ishii
K
K
Kume
N
N
Narumiya
S
S
Kawai
C
C
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000517:prevention & control*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008054:Lipid Peroxides / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000627:therapeutic use*; D011341:Probucol / Q000627:therapeutic use*; D011817:Rabbits
D008054:Lipid Peroxides; D008074:Lipoproteins; D010636:Phenols; D011341:Probucol