© 1995 American Heart Association, Inc.
Articles |
Recombinant Apolipoprotein A-IMilano Dimer Inhibits Carotid Intimal Thickening Induced by Perivascular Manipulation in Rabbits
From the Institute of Pharmacological Sciences and Center E. Grossi Paoletti, University of Milano (Italy).
Correspondence to Dr Maurizio Soma, Institute of Pharmacological Sciences, via Balzaretti 9, 20133 Milano, Italy.
Abstract Apolipoprotein A-IMilano
(apoA-IM), a natural variant of apolipoprotein A-I
(apoA-I), confers to the carriers a significant protection against
vascular disease. The antiatherogenic activity of a recombinant
disulfide-linked apoA-IM dimer
(rA-IM/A-IM) was analyzed in vivo by
evaluating its effect on neointimal formation induced by
periarterial manipulation in 1% cholesterol–fed rabbits. A flexible
collar was applied around the carotid artery 21 days after the
beginning of the dietary regimen, and animals were killed 10 days
later. Rabbits were injected five times with reconstituted high-density
lipoprotein containing egg phosphatidylcholine (EPC) and
rA-IM/A-IM (119 mg EPC+40 mg protein per
dose) or with EPC liposomes (119 mg EPC per dose) beginning either 5
days before or at the day of collar positioning. Neither treatment
affected plasma cholesterol levels. A significant intimal thickening
was observed in control animals; the intima-to-media (I/M) ratio was
0.63±0.11 versus 0.03±0.05 for the sham-operated contralateral
arteries. Neointimal formation was markedly inhibited in animals
pretreated with rA-IM/A-IM before lesion
induction (I/M, 0.26±0.19) but not in those in which treatment
began the day of collar insertion (I/M, 0.74±0.14). EPC liposomes did
not affect neointimal formation (I/M, 0.50±0.14 and
0.51±0.07 in the two treatment groups). Proliferation of smooth muscle
cells, assessed by direct incorporation of bromo-2'-deoxyuridine (BrdU)
into replicating DNA, was reduced by 
30% and 75% in the intimal
and medial tissues of
rA-IM/A-IM–pretreated rabbits. Thus, a
short-term treatment with rA-IM/A-IM
inhibits smooth muscle cell proliferation and intimal thickening in
rabbits, providing evidence for the potential use of
rA-IM/A-IM in the treatment of
atherosclerosis.
Key Words: recombinant apolipoproteins • smooth muscle cell proliferation • atherosclerosis • restenosis
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