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Hum. Reprod. Advance Access originally published online on November 9, 2007
Human Reproduction 2008 23(2):440-446; doi:10.1093/humrep/dem247
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation

Aki Isobe1,2, Takashi Takeda1,3,5, Masahiro Sakata1, Asako Miyake1, Toshiya Yamamoto2, Ryoko Minekawa1, Fumihito Nishimoto1, Yoko Oskamoto1, Cheryl Lyn Walker4 and Tadashi Kimura1

1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan 2 Department of Obstetrics and Gynecology, Sakai Municipal Hospital, Sakai, Osaka, Japan 3 Department of Gynecology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan 4 Department of Carcinogenesis, University of Texas and MD Anderson Cancer Center, Smithville, TX, USA

5 Correspondence address. Tel: +81 6 6879 3351; Fax: +81 6 6879 3359; E-mail: take{at}gyne.med.osaka-u.ac.jp

BACKGROUND: Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure.

METHODS: In this study, we investigated the potential role of Ang II (1–1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT–PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II.

RESULTS: Ang II induced ELT-3 leiomyoma cell proliferation (P < 0.01) and the expression of Ang II type 1 receptor (AT1R) and AT2R mRNA and protein was confirmed. Regarding the intracellular signaling pathway, the Ang II-induced cell proliferation was AT1R-, epidermal growth factor receptor-, extracellular-regulated kinase- and protein kinase C-dependent but was not dependent on the AT2R or phosphatidylinositol-3 kinase or JAK kinase. The AT1R blocker telmisartan, effectively repressed Ang II-induced and estradiol-induced cell proliferation (P < 0.01). AT1R, but not AT2R, plays a role in Ang II-induced ELT-3 cell proliferation.

CONCLUSIONS: These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells.

Key words: angiotensin II/angiotensin II type 1 receptor blocker/signal transduction/telmisartan/uterine leiomyoma

Submitted on December 26, 2006; resubmitted on June 19, 2007; accepted on June 24, 2007.


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