To examine the therapeutic effect of Vactosertib, a small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor (activin receptor-like kinase-5, ALK5), in an experimental model of Peyronie's disease (PD) and determining anti-fibrotic mechanisms of Vactosertib in primary fibroblasts derived from human PD plaques.
Male rats were randomly divided into three groups (n=6 per group); control rats without treatment; PD rats receiving vehicle; and PD rats receiving Vactosertib (10 mg/kg). PD-like plaques were induced by administering 100 μL of each of human fibrin and thrombin solutions into the tunica albuginea on days 0 and 5. Vactosertib was given orally five times a week for 2 weeks. On day 30, we performed electrical stimulation of the cavernous nerve to measure erectile function, and the penis was obtained for histological examination. Fibroblasts isolated from human PD plaques were used to determine the anti-fibrotic effects of Vactosertib in vitro.
Vactosertib induced significant regression of fibrotic plaques in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which recovered erectile function. Vactosertib also abrogated TGF-β1-induced enhancement of extracellular matrix protein production and hydroxyproline content in PD fibroblasts in vitro by hindering the TGF-β1-induced Smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast transdifferentiation.
In view of the critical role of TGF-β and the Smad pathway in the pathogenesis of PD, inhibition of this pathway with an ALK5 inhibitor may represent a novel, targeted therapy for PD.
The world journal of men's health. 2019 Aug 27 [Epub ahead of print]
Kang Moon Song, Doo Yong Chung, Min Ji Choi, Kalyan Ghatak, Nhat Minh Nguyen, Anita Limanjaya, Mi Hye Kwon, Jiyeon Ock, Guo Nan Yin, Dae Kee Kim, Ji Kan Ryu, Jun Kyu Suh
National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea., Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewah Womans University, Seoul, Korea., National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea. ., National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea. .