Fasudil Inhibits the Proliferation and Contractility and Induces Cell Cycle Arrest and Apoptosis of Human Endometriotic Stromal Cells: A Promising Agent for the Treatment of Endometriosis

Author:

Tsuno Akitoshi1,Nasu Kaei1,Kawano Yukie1,Yuge Akitoshi1,Li Haili1,Abe Wakana1,Narahara Hisashi1

Affiliation:

1. Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Oita 879-5593, Japan

Abstract

AbstractContext:During the development of endometriotic lesions, excess fibrosis may lead to scarring and to the alterations of tissue function that are the characteristic features of this disease. Enhanced extracellular matrix contractility of endometriotic stromal cells (ECSC) mediated by the mevalonate-Ras homology (Rho)/Rho-associated coiled-coil-forming protein kinase (ROCK) pathway has been shown to contribute to the pathogenesis of endometriosis.Design:To assess the use of fasudil, a selective ROCK inhibitor, for the medical treatment of endometriosis-associated fibrosis, the effects of this agent on the cell proliferation, apoptosis, cell cycle, morphology, cell density, and contractility of ECSC were investigated. The effects of fasudil on the expression of contractility-related, apoptosis-related, and cell cycle-related molecules in ECSC were also evaluated.Results:Fasudil significantly inhibited the proliferation and contractility of ECSC and induced the cell cycle arrest in the G2/M phase and apoptosis of these cells. Morphological observation revealed the suppression of ECSC attachment to collagen fibers and decrease of cell density by fasudil. The expression of α-smooth muscle actin, RhoA, ROCK-I, and ROCK-II proteins was inhibited by fasudil administration. The expression of the antiapoptotic factors, Bcl-2 and Bcl-XL, in two-dimensional cultured ECSC were down-regulated by the addition of fasudil, whereas, the expression of p16INK4a and p21Waf1/Cip1 was up-regulated by the addition of fasudil.Conclusions:The present findings suggest that fasudil is a promising agent for the treatment of endometriosis. The inhibition of cell proliferation, contractility, and myofibroblastic differentiation, the attenuation of attachment to collagen fibers, the decrease of cell density, and the induction of cell cycle arrest and apoptosis of ECSC are involved in the active mechanisms of fasudil.

Publisher

The Endocrine Society

Subject

Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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