Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway
Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway
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DOI：
10.1210/jc.2002-021582
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发表时间：
2003-08-01
影响因子：
5.8
通讯作者：
Mizutani, S
中科院分区：
文献类型：
--
作者：
Ino, K;Uehara, C;Mizutani, S
血管紧张素 II (Ang II) 是肾素血管紧张素系统的生物活性肽，不仅发挥血管收缩剂的作用，而且还发挥生长促进剂的作用。在人胎盘中，1型Ang II受体（AT(1)R）主要在滋养层细胞中表达，我们之前报道过氨肽酶A（APA），一种将Ang II转化为Ang III的细胞表面肽酶，也在正常和肿瘤滋养层细胞中表达。然而，Ang II 和 APA 在滋养层功能中的作用仍有待阐明。在本研究中，我们检测了 Ang II 对滋养层样 BeWo 绒毛膜癌细胞增殖和 APA 表达的影响。用 Ang II 处理 BeWo 细胞，以剂量依赖性方式显着增加 DNA 合成。通过 Northern 印迹、流式细胞术和酶活性测定分析，Ang II 还增强了 BeWo 细胞中的 APA mRNA 和细胞表面表达。 Ang II 诱导的增殖和 APA 上调可被 AT(1)R 拮抗剂坎地沙坦阻断，但不能被 AT(2)R 拮抗剂 PD123319 阻断。此外，这些 Ang II 效应被蛋白激酶 C 抑制剂双吲哚马来酰亚胺 I 和 MAPK 抑制剂 PD98059 消除。使用绒毛膜癌组织的免疫组织化学证明APA在体内AT(1)R阳性细胞滋养层细胞的细胞表面表达。通过这些发现，我们证明 Ang II 通过与蛋白激酶 C/MAPK 依赖性信号通路相关的 AT(1)R 刺激滋养层细胞的增殖，并且 Ang II 降解酶 APA 在 Ang II 诱导的细胞增殖过程中上调。这些观察结果表明局部肾素-血管紧张素系统，特别是Ang II-AT(1)R-APA系统对人绒毛膜癌细胞生长的可能调节机制。
Angiotensin II (Ang II) is a bioactive peptide of the reninangiotensin system, exerting its actions not only as a vasoconstrictor, but also as a growth promoter. In human placenta, type 1 Ang II receptors ( AT(1)R) are predominantly expressed in trophoblasts, and we previously reported that aminopeptidase A (APA), a cell surface peptidase that converts Ang II to Ang III, is also expressed in both normal and neoplastic trophoblasts. However, the roles of Ang II and APA in trophoblast function remain to be clarified. In the present study we examined the effects of Ang II on proliferation and APA expression in trophoblast-like BeWo choriocarcinoma cells. Treatment of BeWo cells with Ang II significantly increased DNA synthesis in a dose-dependent manner. Ang II also enhanced APA mRNA and cell surface expression in BeWo cells analyzed by Northern blotting, flow cytometry, and enzyme activity assay. The Ang II-induced proliferation and APA up-regulation were blocked by the AT(1)R antagonist candesartan, but not by the AT(2)R antagonist PD123319. Furthermore, these Ang II effects were abolished by the protein kinase C inhibitor bisindolylmaleimide I and the MAPK inhibitor PD98059. Immunohistochemistry using choriocarcinoma tissues demonstrated that APA was expressed on the cell surface of AT(1)R-positive cytotrophoblastic cells in vivo. With these findings we demonstrate that Ang II stimulates the proliferation of trophoblastic cells via AT(1)R that are linked to protein kinase C/MAPK-dependent signaling pathways, and that the Ang II-degrading enzyme APA is up-regulated during Ang II-induced cell proliferation. These observations suggest the possible regulatory mechanism by the local renin-angiotensin system, especially the Ang II-AT(1)R-APA system, for the growth of human choriocarcinoma cells.