Atherosclerosis is a fundamental cause of life-threatening disorders, such as
ischemic heart disease or
stroke. Therefore, prevention and treatment of
atherosclerosis is a matter of importance. In atherosclerotic lesions, there are many foam cells which contain large amounts of
cholesteryl ester. In particular, most of these foam cells in the early stage of
atherosclerosis derive from monocytes/macrophages. Today, foam cell transformation of macrophages in subendothelial space is considered to occur by a mechanism in which macrophages take up
oxidized low density lipoprotein. We have already discovered that
atherosclerosis of Watanabe heritable hyperlipidemic rabbits, an animal model for hereditary
hyperlipidemia and severe
atherosclerosis, could be prevented by
probucol. This
drug was originally developed as an
antioxidant, and the mechanism of prevention of
atherogenesis with this
drug is considered that it prevents oxidative modification of
LDL. On the other hand,
probucol also causes regression of
xanthoma in patients with
familial hypercholesterolemia. This effect implies that
probucol can be effective for treatment of atheromatous lesions, because
xanthoma is a lesion which consists of macrophage-derived foam cells. However, the precise mechanism of
probucol in causing regression of
xanthoma has not been clarified. Considering these observations, we paid special attention to the oxidative modification of
high density lipoprotein (HDL). HDL makes contact with foam cells in subendothelial space and stimulates efflux of
cholesterol. This is the very place where oxidative modification of
LDL is considered to occur. Therefore, it is rational to attempt to determine what would happen when HDL is oxidized and whether
probucol could prevent oxidative modification of HDL.(ABSTRACT TRUNCATED AT 250 WORDS)