HYDROXYPROPYL-BETA-CYCLODEXTRIN-MEDIATED EFFLUX OF 7-KETOCHOLESTEROL FROM MACROPHAGE FOAM CELLS

Atherosclerosis involves the arterial accumulation of lipid-laden ''fo am cells'' containing oxidized and unoxidized sterols and their esters (Mattsson-Hulten, L., Lindmark, H., Diczfalusy, U., Bjorkhem, I., Ott osson, M., Liu, Y., Bondjers, G., and Wiklund, O, (1996) J, Clin, Inve st, 97, 461-8), Oxidized sterols are probably critical to atherogenesi s because they inhibit cholesterol removal from cells and are cytotoxi c. We recently reported that there is deficient induction of cellular cholesterol efflux by apolipoprotein A-I, the main initial acceptor of cellular cholesterol from macrophages loaded in vitro with oxidized l ow density lipoprotein (Kritharides, L., Jessup, W., Mander, E., and D ean, R. T. (1995) Arterioscler. Thromb. 15, 276-289). There was an eve n more marked impairment of the release of 7-ketocholesterol which is a major oxysterol in these cells and in human atherosclerotic lesions. Here we show that hydroxypropyl-beta-cyclodextrin can induce selectiv e efflux of 7-ketocholesterol. Efflux of 7-ketocholesterol was time an d concentration dependent, and the rate of its removal was 50-fold gre ater for hydroxypropyl-beta-cyclodextrin than for apolipoprotein A-I. Over a defined range of concentrations (0-5 mg/ml), efflux of 7-ketoch olesterol was preferred over that of cholesterol and occurred without cell toxicity. Efflux of free 7-ketocholesterol was associated with de creased intracellular free and esterified 7-ketocholesterol, Hydroxypr opyl-beta-cyclodextrin also enhanced efflux of other oxysterols. The p hysical solubilization of 7-ketocholesterol by the cyclodextrin was mu ch greater than that of cholesterol, in accordance with its differenti al effects on efflux, These data highlight the importance of extracell ular sterol solubilization in the efflux of cellular oxysterols and th e mobilization of intracellular free and esterified oxysterol pools in macrophages loaded with oxidized low density lipoprotein. Synthetic s terol-solubilizing agents such as hydroxypropyl-beta-cyclodextrin are thus potential prototypes for the further development of oxysterol-rem oving agents.