マクロファージにおけるリポタンパク代謝 ＷＨＨＬウサギの成績を中心に

Abstract

The foam cell has been recognized as a characteristic feature of xanthomas and atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore, the macrophage 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 native lipoprotein, such as β-VLDL and WHHL-VLDL and also certain chemically modified lipoproteins, such as acetylated LDL and malondialdehyde-treated LDL through the process of receptor-mediated endocytosis and thereby they become foam cells. Yet modified LDL has not been demonstrated to exist in the body. Recently oxidized LDL is 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 causes a regression of cutaneous and tendon xanthomas in homoyzgous FH patients.Therefore we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous WHHL-rabbits, an animal model for familial hypercholesterolemia. Six months after treatment with probucol, the percentage of surface area of total thoracic aorta with visible plaques was 7.0±6.3%, whereas 54.2±18.8% in untreated WHHL-rabbits in spite of no reduction of plasma cholesterol level. LDL isolated from WHHL rabbits under treatment with probucol were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages. Our study suggests the possibility that oxidized LDL is the true form of modified LDL that produces foam cells and atherosclerosis in vivo.