Circulation, Vol 90, 1935-1941, Copyright © 1994 by American Heart Association
S Ameli, A Hultgardh-Nilsson, B Cercek, PK Shah, JS Forrester, H Ageland and J Nilsson
BACKGROUND: Several epidemiological studies have shown an inverse relation
between high-density lipoprotein (HDL) cholesterol levels and coronary
heart disease. Recently, observational studies have suggested a similar
inverse relation between HDL and restenosis after coronary balloon
angioplasty. Despite these observations, it is unclear whether this inverse
relation reflects a direct vascular protective effect of HDL or
apolipoprotein (apo) A-I, the major apolipoprotein component of HDL.
Therefore, to determine whether HDL directly influences neointima
formation, we investigated the effect of recombinant apo A-I Milano (apo
A-I M), a mutant of human apo A-I with Arg-173 to Cys substitution, on
intimal thickening after balloon injury in cholesterol- fed rabbits.
METHODS AND RESULTS: Cholesterol feeding was initiated 18 days before
injury and continued until the time of death. Eight rabbits received
intravenous injections of 40 mg of apo A-I M linked to a phospholipid
carrier on alternate days, beginning 5 days before and continuing for 5
days after balloon injury of femoral and iliac arteries. Eight rabbits
received the carrier alone, and four received neither apo A-I M nor the
carrier. Three weeks after balloon injury, apo A-I M-treated rabbits had
significantly reduced intimal thickness compared with the two control
groups (mean +/- SD): 0.49 +/- 0.29 versus 1.14 +/- 0.38 mm2 and 1.69 +/-
0.43 mm2, P < .002 by ANOVA). The intima-to-media ratio was also
significantly reduced by apo A-I M (0.7 +/- 0.2 versus 1.5 +/- 0.5 and 2.1
+/- 0.1, P < .002 by ANOVA) compared with the two controls. The fraction
of intimal lesion covered by macrophages, as identified by
immunohistochemistry using macrophage- specific monoclonal antibody, was
significantly less in apo A-I M- treated rabbits compared with
carrier-treated animals (25.3 +/- 17% versus 59.4 +/- 12.3%, P < .005).
Aortic cholesterol content, measured in an additional 10 rabbits, did not
differ significantly between apo A- I M-treated animals (n = 5) and
carrier-treated controls (n = 5). CONCLUSIONS: Apo A-I M significantly
reduced intimal thickening and macrophage content after balloon injury in
cholesterol-fed rabbits without a change in arterial total cholesterol
content. Although the precise mechanism of action remains to be defined,
these findings are consistent with a direct vascular effect of apo A-I,
which could have potential therapeutic implications.
ARTICLES
Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
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