Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. II.     Cellular composition and proliferation.

    抗氧化剂普罗布考治疗食饵性高胆固醇血症非人灵长类动物（猕猴属）模型，胸主动脉内膜损伤面积减小，血浆LDL对氧化的抵制性增强。对普罗布考治疗高胆固醇血症动物模型损伤面积减小相关的细胞与分子变化进行数据分析。普罗布考治疗动物的损伤较不成熟并发生脂质分布的改变。与对照组高胆固醇血症动物相比，普罗布考治疗动物的内膜与间质中存在大量脂质负荷的平滑肌细胞和较少脂质负荷的巨噬细胞。在对照与普罗布考组中，巨噬细胞在大多数损伤中起主要作用，但在普罗布考治疗动物的下胸与上腹动脉处，巨噬细胞与平滑肌细胞的比值发生下降。普罗布考治疗动物所有主动脉损伤部位处于循环周期的细胞有35%至80%的比例减少。两组中，巨噬细胞与平滑肌细胞呈PCNA阳性，但大多数（60%）为巨噬细胞。髂骨动脉的PCNA-阳性细胞含量无差异。普洛布考用药之前损伤最为严重。

    因此，抗氧化剂普罗布考在治疗动脉粥样硬化中的潜在疗效可能与其改变早期炎症及纤维化进程有关。但这种作用是否与普罗布考的抗氧化作用直接相关尚未可知。

    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.