From the Atherosclerosis Research Center (P.K.S., S.K., M.C.F., B.C.),
Division of Cardiology, Burns and Allen Research Institute, Cedars-Sinai
Medical Center and UCLA School of Medicine, Los Angeles, Calif; King Gustav V
Research Institute (J.N., A.H., F.K.), Karolinska Hospital, Stockholm, Sweden;
and Pharmacia-Upjohn (H.A., J.J.), Stockholm, Sweden.
Correspondence to Prediman K. Shah, MD, Cedars-Sinai Medical Center, Room 5347, 8700 Beverly Boulevard, Los Angeles, CA 90048. E-mail shahp{at}csmc.edu
Background—We previously reported
marked inhibitory effects of recombinant apolipoprotein
(apo) A-IMilano/phospholipid complex
(A-IMilano/PC) on neointimal lesions in
balloon-injured iliofemoral arteries of
hypercholesterolemic rabbits. In this study, we tested
the hypothesis that apo A-IMilano/PC would inhibit aortic
atherosclerosis in apo E–deficient mice.
Methods and Results—Thirty-five apo E–deficient mice fed a
high-cholesterol diet were included in the study. Control
mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received
18 injections of either 40 mg/kg apo A-IMilano/PC (n=15) or
PC only (n=5) intravenously every other day from 20 weeks
until death at 25 weeks. Aortic atherosclerosis was
identified with Sudan IV staining. Lipid and macrophage
contents of the aortic sinus plaques were measured after oil-red O and
Mac-1 antibody staining, respectively, and quantified with computed
morphometry. In control mice, from 20 to 25 weeks, aortic
atherosclerosis increased by 59% (11±1% versus
17±5% of the aortic surface, P=.002), and lipid
content increased by 45% (22±8% versus 32±6% of plaque area,
P=.02) without a significant change in
macrophage content (10.8±2% versus 13.2±6%). Compared with
20-week-old untreated control mice, PC only–treated mice at 25 weeks
demonstrated a 32% increase in aortic atherosclerosis
(11±1% versus 15±4%, P=.01) and an increase in lipid
content (22±8% versus 47±3%, P<.0001) without a
change in macrophage content (10.8±2% versus 11±2%). In
comparison with 20-week-old untreated control mice, 25-week-old apo
A-IMilano/PC–treated mice demonstrated no increase in
aortic atherosclerosis (11±1% versus 10±4%,
P=NS), a 40% reduction in lipid content (22±8% versus
13±8%, P=.01), and a 46% reduction in
macrophage content (10.8±2% versus 5.8±2.9%;
P=.03). Serum cholesterol levels were
markedly elevated in all groups and did not change significantly with
apo A-IMilano/PC or PC only. In vitro, apo
A-IMilano/PC stimulated cholesterol efflux from
cholesterol-loaded FU5AH hepatoma cell lines in a
dose-dependent manner, whereas PC only or PC-free apo
A-IMilano had no effect.
Conclusions—Recombinant A-IMilano/PC prevented
progression of aortic atherosclerosis and reduced lipid
and macrophage content of plaques in apo E–deficient mice
despite severe hypercholesterolemia. Thus,
A-IMilano/PC may have a role in inhibiting progression and
promoting stabilization of atherosclerosis.
© 1998 American Heart Association, Inc.
Basic Science Reports
Effects of Recombinant Apolipoprotein A-IMilano on Aortic Atherosclerosis in Apolipoprotein E–Deficient Mice
Key Words: apolipoproteins • atherosclerosis • hypercholesterolemia
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