Greenstein S M, Sun S, Calderon T M, Kim D Y, Schreiber T C, Schechner R S, Tellis V A, Berman J W
Department of Surgery, Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, 111 East 210th Street, Bronx, New York 10467, USA.
J Surg Res. 2000 Jun 15;91(2):123-9. doi: 10.1006/jsre.2000.5919.
Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.
动脉血管壁成分对脂质代谢紊乱的免疫/炎症反应被认为与动脉粥样硬化的发病机制有关。霉酚酸酯（MMF）是一种用于临床移植的抗增殖药物，已被证明可抑制平滑肌细胞（SMC）增殖，并减少单核细胞向慢性炎症部位的募集。本研究旨在确定MMF对胆固醇诱导损伤后动脉粥样硬化斑块形成的影响。给新西兰白兔喂食含0.5%胆固醇和8%花生油的高胆固醇饮食。实验组（n = 10）皮下注射MMF（80 mg/kg/天）；对照组（n = 10）注射安慰剂。12周时采集主动脉进行免疫组织化学分析。通过与抗α平滑肌肌动蛋白单克隆抗体（mAb）反应鉴定SMC。用mAb RAM 11检测单核细胞/巨噬细胞。使用计算机辅助图像分析测量中膜和新生内膜的横截面积。通过将细胞数量除以斑块面积计算新生内膜中SMC和巨噬细胞/泡沫细胞的密度。与高胆固醇饮食开始前的水平相比，总胆固醇、甘油三酯、高密度脂蛋白和低密度脂蛋白显著升高，但MMF治疗组和未治疗组之间无显著差异。MMF治疗组主动脉组织切片的新生内膜面积（0.586 +/- 0.602 mm²）与对照动物（1.082 +/- 0.621 mm²）相比显著降低（P < 0.05）。对照组新生内膜SMC和单核细胞/巨噬细胞的密度分别为778 +/- 293和341 +/- 90个细胞/mm²。MMF治疗显著减少了新生内膜SMC的数量（506 +/- 185个细胞/mm²）（P < 0.05）。MMF治疗后单核细胞/巨噬细胞的数量也减少了（260 +/- 124个细胞/mm²），但差异不显著。我们的结果表明，在动脉粥样硬化的高胆固醇血症模型中，给予MMF可显著减少新生内膜SMC的积聚和斑块形成。
