Chang M Y, Sasahara M, Chait A, Raines E W, Ross R
Department of Medicine, University of Washington, Seattle 98195-7470, USA.
Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1631-40. doi: 10.1161/01.atv.15.10.1631.
In nonhuman primates (Macaca nemestrina) treated with the antioxidant probucol during diet-induced hypercholesterolemia, intimal lesion area in the thoracic aorta was decreased, with increased resistance of plasma LDL to oxidation. The cellular and molecular changes associated with the decrease in lesion size in the probucol-treated hypercholesterolemic animals are quantitatively evaluated in this study. Lesions from the probucol-treated animals appear less mature and have altered lipid distribution. Abundant lipid-laden smooth muscle cells are found in the intima and media of the probucol-treated animals, with fewer medial lipid-laden macrophages, compared with lesions at similar sites in the control hypercholesterolemic animals. In both the control and probucol-treated animals, macrophages are the predominant cells in most lesions, but the ratio of macrophages to smooth muscle cells is decreased in the lower thoracic and upper abdominal aortic sites in the probucol-treated animals. Lesions at all aortic sites in the probucol-treated animals have a 35% to 80% reduction in the percentage of cells in cell cycle traverse, as indicated by immunostaining for proliferating cell nuclear antigen (% PCNA-positive). In both groups, macrophages and smooth muscle cells are PCNA-positive, but the majority (> 60%) are macrophages. No difference in % PCNA-positive cells is seen in the iliac arteries, where the most advanced lesions were present at the time probucol administration was initiated. Limited Northern analysis of growth-regulatory molecules possibly involved in the cellular changes associated with lesions shows a 30% to 50% decrease in mRNA levels of platelet-derived growth factor (PDGF) B-chain, PDGF beta-receptor, colony-stimulating factor type 1, and monocyte chemotactic protein 1. Thus, a potential role for an antioxidant such as probucol in the treatment of atherosclerosis may be to alter the early inflammatory fibroproliferative processes of the disease. Whether these effects are directly related to the antioxidant properties or some other activity of probucol is not yet known.
在饮食诱导的高胆固醇血症期间用抗氧化剂普罗布考治疗的非人灵长类动物（食蟹猴）中，胸主动脉内膜病变面积减小，血浆低密度脂蛋白（LDL）对氧化的抵抗力增加。本研究定量评估了普罗布考治疗的高胆固醇血症动物中与病变大小减小相关的细胞和分子变化。普罗布考治疗动物的病变显得不太成熟，脂质分布也发生了改变。与对照高胆固醇血症动物相似部位的病变相比，在普罗布考治疗动物的内膜和中膜中发现了大量充满脂质的平滑肌细胞，中膜中充满脂质的巨噬细胞较少。在对照动物和普罗布考治疗动物中，巨噬细胞都是大多数病变中的主要细胞，但在普罗布考治疗动物的胸主动脉下段和腹主动脉上段部位，巨噬细胞与平滑肌细胞的比例降低。通过增殖细胞核抗原免疫染色（%PCNA阳性）表明，普罗布考治疗动物所有主动脉部位病变中处于细胞周期进程的细胞百分比降低了35%至80%。在两组中，巨噬细胞和平滑肌细胞都是PCNA阳性，但大多数（>60%）是巨噬细胞。在给药普罗布考时存在最晚期病变的髂动脉中，%PCNA阳性细胞未见差异。对可能参与与病变相关细胞变化的生长调节分子进行的有限Northern分析显示，血小板衍生生长因子（PDGF）B链、PDGFβ受体、1型集落刺激因子和单核细胞趋化蛋白1的mRNA水平降低了30%至50%。因此，抗氧化剂如普罗布考在动脉粥样硬化治疗中的潜在作用可能是改变该疾病早期的炎症性纤维增生过程。这些作用是否与普罗布考的抗氧化特性或其他一些活性直接相关尚不清楚。
