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Vactosertib, a Novel, Orally Bioavailable Activin Receptor-Like Kinase 5 Inhibitor, Promotes Regression of Fibrotic Plaques in a Rat Model of Peyronie's Disease

The World Journal of Men′s Health 2020년 38권 4호 p.552 ~ 563
Song Kang-Moon, 정두용, 최민지, Ghatak Kalyan, Minh Nguyen Nhat, Limanjaya Anita, 권미혜, Ock Ji-Yeon, Yin Guo Nan, 김대기, 류지간, 서준규,
소속 상세정보
 ( Song Kang-Moon ) - Inha University School of Medicine Department of Urology
정두용 ( Chung Doo-Yong ) - Inha University School of Medicine Department of Urology
최민지 ( Choi Min-Ji ) - Inha University School of Medicine Department of Urology
 ( Ghatak Kalyan ) - Inha University School of Medicine Department of Urology
 ( Minh Nguyen Nhat ) - Inha University School of Medicine Department of Urology
 ( Limanjaya Anita ) - Inha University School of Medicine Department of Urology
권미혜 ( Kwon Mi-Hye ) - Inha University School of Medicine Department of Urology
 ( Ock Ji-Yeon ) - Inha University School of Medicine Department of Urology
 ( Yin Guo Nan ) - Inha University School of Medicine Department of Urology
김대기 ( Kim Dae-Kee ) - Ewha Womans University College of Pharmacy
류지간 ( Ryu Ji-Kan ) - Inha University School of Medicine Department of Urology
서준규 ( Suh Jun-Kyu ) - Inha University School of Medicine Department of Urology

Abstract


Purpose: 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.

Materials and Methods: 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.

Results: 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.

Conclusions: 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.

키워드

Activin receptors; Fibrosis; Peyronie's disease; Transforming growth factor beta

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