Ferns G A, Forster L, Stewart-Lee A, Konneh M, Nourooz-Zadeh J, Anggård E E
William Harvey Research Institute, Charterhouse Square, London, United Kingdom.
Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11312-6. doi: 10.1073/pnas.89.23.11312.
Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.
再狭窄是球囊血管成形术后常见的长期并发症。尽管平滑肌细胞是闭塞性病变的主要成分，但巨噬细胞源性泡沫细胞通常也大量存在。后者有可能加速再闭塞的速度，因为它们能分泌许多强效细胞因子和生长因子，这些因子可能会促使细胞进入新生内膜或导致新生内膜细胞增殖。巨噬细胞源性泡沫细胞的形成依赖于通过清道夫受体介导的途径摄取修饰的低密度脂蛋白。泡沫细胞的形成伴随着平滑肌细胞有丝分裂原和趋化因子的释放。我们研究了脂溶性抗氧化剂普罗布考对喂食胆固醇的家兔经球囊导管插入的颈动脉的影响，以评估氧化过程在再狭窄中的重要性。5周后，与仅接受胆固醇的家兔相比，喂食含2%胆固醇的1%普罗布考的家兔血清胆固醇水平降低了32%（P<0.05）。普罗布考使新生内膜巨噬细胞的积聚减少了68%（P<0.001），使绝对内膜大小减少了51%（P<0.05），并使内膜/中膜厚度比降低了51%。这些抑制作用与血清普罗布考浓度直接相关，似乎与普罗布考的降胆固醇活性无关。这些数据表明，活性氧可能参与了内膜对损伤的反应，而抗氧化剂，如普罗布考，作为再狭窄的抑制剂可能具有治疗作用。
