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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

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

Address all correspondence and requests for reprints to: Kazuhiko Ino, M.D., Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: kazuino{at}med.nagoya-u.ac.jp.

Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, exerting its actions not only as a vasoconstrictor, but also as a growth promoter. In human placenta, type 1 Ang II receptors (AT₁R) 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 AT₁R antagonist candesartan, but not by the AT₂R 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 AT₁R-positive cytotrophoblastic cells in vivo. With these findings we demonstrate that Ang II stimulates the proliferation of trophoblastic cells via AT₁R 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-AT₁R-APA system, for the growth of human choriocarcinoma cells.

Abbreviations: ACE, Angiotensin-converting enzyme; Ang II, angiotensin II; APA, aminopeptidase A; AT₁R, angiotensin type 1 receptor; AT₂R, angiotensin type 2 receptor; BAPTA, 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetic acid tetraacetoxymethyl ester; Bis I, bisindolylmaleimide I; BrdU, bromodeoxyuridine; EGFR, epidermal growth factor receptor; FACS, fluorescence-activated cell sorting; FCS, fetal calf serum; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PKC, protein kinase C; RAS, renin-angiotensin system; VSMC, vascular smooth muscle cell.

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