Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study
Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study
复制标题
DOI：
10.1016/s0024-3205(01)01352-2
复制
发表时间：
2001-10-19
期刊：
影响因子：
6.1
通讯作者：
Karaki, H
中科院分区：
文献类型：
--
作者：
Murata, T;Yamawaki, H;Karaki, H
我们试图利用器官培养系统来确定阿霉素，一种常用的抗癌药物对血管内皮细胞的慢性影响。0.3mU阿霉素作用7d后，肠系膜动脉内皮细胞胞核变圆、浓集，TUNEL染色阳性，提示DNA损伤，诱导细胞凋亡。而P物质引起的内皮依赖性松弛和内皮型一氧化氮合酶(ENOS)基因的表达与对照组无明显差异。高浓度(1um)阿霉素处理的动脉内皮细胞在处理后第3天出现细胞凋亡和核损伤，内皮细胞从血管壁内膜脱落和剥离。阿霉素治疗后第5天观察血管内皮依赖性松弛功能受损情况。此外，在该浓度的阿霉素作用下，可观察到平滑肌层中的细胞凋亡变化。分离的牛主动脉内皮细胞(BAECs)和A7r5血管平滑肌细胞的DNA片段化进一步证实了细胞的凋亡现象，并且BAECs比A7r5细胞对阿霉素的凋亡作用更敏感。这些结果表明，治疗浓度的阿霉素慢性治疗可诱导内皮细胞的凋亡和损伤，从而降低内皮依赖性的松弛。(C)2001 Elsevier Science Inc.保留所有权利。
We have attempted to determine the chronic effects of doxorubicin, a commonly used anticancer agent, on vascular endothelium using an organ culture system. In rabbit mesenteric arteries treated with 0.3 muM doxorubicin for 7 days, rounding and concentrated nuclei and TUNEL-positive staining were observed in endothelial cells, indicating DNA damage and the induction of apoptosis. However, the endothelium-dependent relaxation induced by substance P and the expression of mRNA encoding endothelial NO synthase (eNOS) did not differ from those in control arteries. In arteries treated with a higher concentration (1 muM) of doxorubicin, apoptosis and damage to nuclei occurred in the endothelial cells at the third day of treatment, and the detachment and excoriation of endothelium from the tunica interna of the vascular wall were also observed. The impairment of endothelium-dependent relaxation was observed at the fifth day of the treatment with 1 muM doxorubicin. Additionally, apoptotic change in the smooth muscle layer was observed at this concentration of doxorubicin. Apoptotic phenomena were further confirmed by DNA fragmentation using isolated bovine aortic endothelial cells (BAECs) and A7r5 vascular smooth muscle cells, and it was revealed that BAECs are more sensitive than A7r5 to the apoptotic effect of doxorubicin. These results suggest that chronic treatment with doxorubicin at therapeutic concentrations induces apoptosis and excoriation of endothelial cells, which diminishes endothelium-dependent relaxation. (C) 2001 Elsevier Science Inc. All rights reserved.