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 (ape) 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 (ape 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 ape 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 mm(2) and 1.69+/-0.43 mm(2), P<.002 by ANOVA). The intimato-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 ape 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.