Ameli S, Hultgardh-Nilsson A, Cercek B, Shah P K, Forrester J S, Ageland H, Nilsson J
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Circulation. 1994 Oct;90(4):1935-41. doi: 10.1161/01.cir.90.4.1935.
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.
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).
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.
多项流行病学研究表明，高密度脂蛋白（HDL）胆固醇水平与冠心病之间呈负相关。最近，观察性研究提示HDL与冠状动脉球囊血管成形术后再狭窄之间也存在类似的负相关。尽管有这些观察结果，但尚不清楚这种负相关是否反映了HDL或HDL的主要载脂蛋白成分载脂蛋白（apo）A-I的直接血管保护作用。因此，为了确定HDL是否直接影响内膜形成，我们研究了重组载脂蛋白A-I米兰型（apo A-I M）（一种人类apo A-I的突变体，精氨酸-173被半胱氨酸取代）对胆固醇喂养兔球囊损伤后内膜增厚情况的影响。
在损伤前18天开始给予胆固醇喂养，并持续至动物死亡。8只兔在股动脉和髂动脉球囊损伤前5天开始，每隔一天静脉注射40mg与磷脂载体结合的apo A-I M，持续至球囊损伤后5天。8只兔仅接受载体注射，4只兔既未接受apo A-I M也未接受载体。球囊损伤3周后，与两个对照组相比，接受apo A-I M治疗的兔内膜厚度显著降低（均值±标准差）：分别为0.49±0.29 与1.14±0.38mm²和1.69±0.43mm²，方差分析P<0.002）。与两个对照组相比，apo A-I M也使内膜与中膜比值显著降低（分别为0.7±0.2与1.5±0.5和2.1±0.1，方差分析P<0.002）。使用巨噬细胞特异性单克隆抗体通过免疫组织化学鉴定，接受apo A-I M治疗的兔内膜病变中被巨噬细胞覆盖的部分显著少于接受载体治疗的动物（25.3±17%与59.4±12.3%，P<0.005）。在另外10只兔中测量的主动脉胆固醇含量，接受apo A-I M治疗的动物（n=5）与接受载体治疗的对照组（n=5）之间无显著差异。
apo A-I M显著降低了胆固醇喂养兔球囊损伤后的内膜增厚和巨噬细胞含量，而动脉总胆固醇含量无变化。尽管确切的作用机制尚待明确，但这些发现与apo A-I的直接血管效应一致，可能具有潜在的治疗意义。
