Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits.
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.


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.
Ameli
S
S
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Hultgardh-Nilsson
A
A
Cercek
B
B
Shah
P K
PK
Forrester
J S
JS
Ageland
H
H
Nilsson
J
J
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001011:Aorta / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D002404:Catheterization / Q000009:adverse effects*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D000906:Antibodies; D016632:Apolipoprotein A-I; D011994:Recombinant Proteins; C080631:apolipoprotein A-I Milano; D002784:Cholesterol