抄録
It has been demonstrated by several lines of studies that oxidized LDL plays an important role in early stage of atherogenesis. The antioxidant, probucol, inhibits oxidative modification of LDL and prevents progression of atherosclerosis in WHHL rabbits. Probucol also has been reported to stimulate regression of atheromatous lesions. In this study, we tried to elucidate the mechanism which probucol stimulates regression of atherosclerosis.
HDL has been reported to stimulate efflux of cholesterol from foam cells by making direct contact with them in subendothelial space, and this is the very place where oxidative modification of LDL is considered to occur. Therefore, it can be strongly speculated that oxidative modification of HDL occurs in vivo. When HDL was incubated with 5 μM cupric ion, the amount of lipid peroxide increased significantly, and he band of apolipoprotein Al on SDS-PAGE disappeared (Fig. 2). Next, we compared native HDL and oxidized HDL concerning their effect to stimulate efflux of cholesterol from foam cells. The results revealed that oxidized HDL stimulated significantly less amount of cholesterol efflux (Fig. 3). These data suggest that oxidative modification of HDL reduces its antiatherogenic property, and probucol might possibly inhibit oxidative modification of HDL in vivo. Thus, the antioxidative effect of probucol on HDL could be an explanation for stimulating regression of atheromatous plaque.
When atheromatous plaques of probucol-treated and non-treated rabbits were compared, the former contained much less number of macrophages. In order to clarify the mechanism of this phenomenon, we prepared mouse peritoneal macrophages pretreated with or without probucol and compared their chemotactic activity using modified Boyden chamber system. As shown in Fig. 4, probucol-treated macrophages showed increased chamotaxis towards LDL compared with control macrophages, and this couldbe an explanation for macrophage-poor-lesions in probucol-treated rabbits. Our current study demonstrated that an antioxidant, probucol, contributed to the regression of atheromatous plaques by at least two different mechanisms.
