粒细胞巨噬细胞集落刺激因子通过改变渡边遗传性高脂血症兔动脉粥样硬化病变的细胞和细胞外成分来预防动脉粥样硬化的进展。

Granulocyte-macrophage colony-stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits.

作者信息

Shindo J, Ishibashi T, Yokoyama K, Nakazato K, Ohwada T, Shiomi M, Maruyama Y

机构信息

First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.

出版信息

Circulation. 1999 Apr 27;99(16):2150-6. doi: 10.1161/01.cir.99.16.2150.

DOI:10.1161/01.cir.99.16.2150

PMID:10217656

Abstract

BACKGROUND

A cytokine network is involved in atherogenesis. This study was conducted to investigate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the development and composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits.

METHODS AND RESULTS

GM-CSF (10 microg. kg-1. d-1) was administered to 4-month-old WHHL rabbits (n=9) 5 days a week for 7.5 months, whereas an equal dose of human serum albumin was administered to controls (n=9). The cholesterol levels were not changed significantly by the treatment. Age-matched 4-month-old rabbits (n=7) had atheromatous plaques over 30.7+/-5.7% of the inner surface area of the aortic arch. After treatment, the percentages of surface atheromatous plaques to total aortic arch area were 45.0+/-12.6% in the GM-CSF group and 74.3+/-11.0% in controls (P<0.0001). Histological examination demonstrated that GM-CSF reduced the ratio of intima to media (P<0.01) and cross-sectional areas of atherosclerotic lesions (P<0.0001). Quantitative analysis indicated a marked decrease in the areas of smooth muscle cells (P=0.0001), collagen (P=0.0001), and extracellular lipid deposits (P<0.05) of atheromatous plaques in GM-CSF-treated rabbits compared with controls. The terminal deoxynucleotidyltransferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method and immunohistochemistry were performed to examine the relationship between decreased atherosclerotic lesions and apoptosis. The percentage of TUNEL-positive cells increased in the GM-CSF group (GM-CSF, 24.1+/-4.4% versus control, 11.6+/-3.2%; P<0.0001). GM-CSF enhanced the apoptosis of smooth muscle cells in the shoulder region and the fibrous cap (P<0.0001), suggesting one of the mechanisms for the antiatherogenic effect.

CONCLUSIONS

GM-CSF altered the composition of atherosclerotic lesions and reduced the atherosclerosis in WHHL rabbits.

摘要

背景

细胞因子网络参与动脉粥样硬化的发生发展。本研究旨在探讨粒细胞-巨噬细胞集落刺激因子（GM-CSF）对渡边遗传性高脂血症（WHHL）兔动脉粥样硬化病变发展及成分的影响。

方法与结果

对9只4月龄的WHHL兔每周5天给予GM-CSF（10μg·kg-1·d-1），持续7.5个月，而对9只对照组兔给予等量的人血清白蛋白。治疗后胆固醇水平无显著变化。年龄匹配的4月龄兔（7只）主动脉弓内表面有30.7±5.7%的粥样斑块。治疗后，GM-CSF组主动脉弓表面粥样斑块占总面积的百分比为45.0±12.6%，对照组为74.3±11.0%（P<0.0001）。组织学检查显示，GM-CSF降低了内膜与中膜的比例（P<0.01）以及动脉粥样硬化病变的横截面积（P<0.0001）。定量分析表明，与对照组相比，GM-CSF治疗的兔动脉粥样斑块中平滑肌细胞面积（P=0.0001）、胶原蛋白面积（P=0.0001）和细胞外脂质沉积面积（P<0.05）显著减少。采用末端脱氧核苷酸转移酶介导的dUTP-地高辛缺口末端标记（TUNEL）法和免疫组化法检测动脉粥样硬化病变减少与细胞凋亡之间的关系。GM-CSF组TUNEL阳性细胞百分比增加（GM-CSF组为24.1±4.4%，对照组为11.6±3.2%；P<0.0001）。GM-CSF增强了肩部区域和纤维帽处平滑肌细胞的凋亡（P<0.0001），提示这是其抗动脉粥样硬化作用的机制之一。