Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide.
Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide.
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DOI：
10.1161/01.res.81.6.970
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发表时间：
1997-12
影响因子：
20.1
通讯作者：
S. Dimmeler;Volker Rippmann;U. Weiland;J. Haendeler;A. Zeiher
中科院分区：
文献类型：
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作者：
S. Dimmeler;Volker Rippmann;U. Weiland;J. Haendeler;A. Zeiher
血管紧张素II(Ang II)在动脉粥样硬化的病理生物学中起重要作用。由于内皮损伤是动脉粥样硬化发病早期的一个关键事件，我们验证了Ang II可能通过激活细胞自杀途径导致细胞凋亡而损伤内皮细胞的假说。人脐静脉内皮细胞(HUVECs)与剂量递增的血管紧张素Ⅱ(Ang II)孵育18h。用组蛋白相关DNA片段特异性的ELISA法检测HUVECs的凋亡率，并用DNA梯状条带和核染色证实。Ang II呈剂量依赖性诱导HUVECs凋亡。同时阻断AT1和AT2受体可阻止血管紧张素转换酶II诱导的细胞凋亡，而单独使用单独的受体阻滞剂并不有效。选择性激动性刺激AT2受体也可剂量依赖性地诱导细胞凋亡。Ang II介导和选择性AT2受体刺激介导的细胞凋亡与caspase-3的激活有关，caspase-3是执行细胞死亡程序的caspase级联反应的中心下游效应器。特异性抑制caspase-3活性可阻断Ang II诱导的细胞凋亡。此外，NO供体硝普钠和S-亚硝青霉胺可完全抑制血管紧张素Ⅱ诱导的细胞凋亡，并消除caspase-3活性。因此，Ang II通过激活执行细胞死亡程序的中央下游效应臂caspase级联来诱导HUVECs的凋亡。NO通过干扰半胱氨酸天冬氨酸氨基转移酶通路的激活，完全阻断Ang II诱导的细胞凋亡。
Angiotensin II (Ang II) importantly contributes to the pathobiology of atherosclerosis. Since endothelial injury is a key event early in the pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure endothelial cells by activation of cellular suicide pathways leading to apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by ELISA specific for histone-associated DNA fragments and confirmed by DNA laddering and nuclear staining. Ang II dose-dependently induced apoptosis of HUVECs. Simultaneous blockade of both the AT1 and AT2 receptor prevented Ang II-induced apoptosis, whereas each individual receptor blocker alone was not effective. Selective agonistic stimulation of the AT2 receptor also dose-dependently induced apoptosis. Ang II-mediated as well as selective AT2 receptor stimulation-mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program. Specific inhibition of caspase-3 activity abrogated Ang II-induced apoptosis. In addition, the NO donors sodium nitroprusside and S-nitrosopenicillamine completely inhibited Ang II-induced apoptosis and eliminated caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of the caspase cascade, the central downstream effector arm executing the cell death program. NO completely abrogated Ang II-induced apoptosis by interfering with the activation of the caspase cascade.