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

Abstract

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 (AT 1 R) and AT 2 R mRNA and protein was confirmed. Regarding the intracellular signaling pathway, the Ang II-induced cell proliferation was AT 1 R-, epidermal growth factor receptor-, extracellular-regulated kinase-and protein kinase C-dependent but was not dependent on the AT 2 R or phosphatidylinositol-3 kinase or JAK kinase. The AT 1 R blocker telmisartan, effectively repressed Ang II-induced and estradiol-induced cell proliferation (P < 0.01). AT 1 R, but not AT 2 R, 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.

Enodthelin 1 Is Elevated in Plasma and Explants From Patients Having Uterine Leiomyomas

“…Angiotensin II is an important blood pressure control pathway that has been linked to growth and proliferation of uterine leiomyoma. Studies utilizing the Eker rat model indicate that ANGII induced ELT3 cell proliferation via upregulation of the AT1R 11,29 and that proliferation was inhibited by AT1R blockade. 11 In the current study, in vitro blockade of the AT1R with Losartan decreased ET-1 secretion in uterine fibroids which supports a role for the renin-angiotensin system in ET-1 secretion from uterine fibroids.…”

Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

“…AngII was used at concentrations of 1, 10, 100 or 1000 nM (9). An active compound, telmisartan, which is a novel, long-acting, selective AT-1 receptor antagonist, was purchased from Sigma-Aldrich (St. Louis, MO, USA) and used at concentrations of 100 and 1000 nM, according to a previous report (24). Transforming growth factor (TGF)-ß1 was purchased from Sigma-Aldrich and was used at a concentration of 10 ng/ml, according to a previous report (25).…”

Polymorphisms of Renin Angiotensin System Genes in Uterine Leiomyomas Among Egyptian Females

“…Ang II-induced proliferation of leiomyoma cells has been shown [26]. Experimental findings in vitro also highlight the potential role of Ang II in the proliferation of leiomyoma cells [27].…”

“…In 2007, Isobe et al [26] investigated the role of Ang II in the proliferation of rat ELT-3 leiomyoma cells (Eker rat uterine leiomyoma-derived smooth muscle cells) in vitro. They found that Ang II significantly induced ELT-3 leiomyoma cell proliferation and the expression of AT1R and AT2R mRNA and protein was confirmed.…”