Volume 271, Number 44,
Issue of November 1, 1996
pp. 27450-27455
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Hydroxypropyl-
-cyclodextrin-mediated Efflux of
7-Ketocholesterol from Macrophage Foam Cells
(Received for publication, March 27, 1996, and in revised form, July 16, 1996)
Leonard
Kritharides
,
Michele
Kus
,
Andrew J.
Brown
,
Wendy
Jessup
and
Roger T.
Dean
From the Cell Biology Unit, The Heart Research Institute,
Camperdown, Sydney, New South Wales, Australia
Atherosclerosis involves the arterial
accumulation of lipid-laden ``foam cells'' containing oxidized and
unoxidized sterols and their esters (Mattsson-Hulten, L., Lindmark, H.,
Diczfalusy, U., Bjorkhem, I., Ottosson, M., Liu, Y., Bondjers, G., and
Wiklund, O. (1996) J. Clin. Invest. 97, 461-8).
Oxidized sterols are probably critical to atherogenesis because they
inhibit cholesterol removal from cells and are cytotoxic. 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
low density lipoprotein (Kritharides, L., Jessup, W., Mander, E., and
Dean, R. T. (1995) Arterioscler. Thromb. 15, 276-289).
There was an even 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-
-cyclodextrin can induce selective efflux of
7-ketocholesterol. Efflux of 7-ketocholesterol was time and
concentration dependent, and the rate of its removal was 50-fold
greater for hydroxypropyl--cyclodextrin than for apolipoprotein A-I.
Over a defined range of concentrations (0-5 mg/ml), efflux of
7-ketocholesterol was preferred over that of cholesterol and occurred
without cell toxicity. Efflux of free 7-ketocholesterol was associated
with decreased intracellular free and esterified 7-ketocholesterol.
Hydroxypropyl--cyclodextrin also enhanced efflux of other
oxysterols. The physical solubilization of 7-ketocholesterol by the
cyclodextrin was much greater than that of cholesterol, in accordance
with its differential effects on efflux. These data highlight the
importance of extracellular sterol solubilization in the efflux of
cellular oxysterols and the mobilization of intracellular free and
esterified oxysterol pools in macrophages loaded with oxidized low
density lipoprotein. Synthetic sterol-solubilizing agents such as
hydroxypropyl--cyclodextrin are thus potential prototypes for the
further development of oxysterol-removing agents.
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