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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

Title
Vactosertib, a Novel, Orally Bioavailable Activin Receptor-Like Kinase 5 Inhibitor, Promotes Regression of Fibrotic Plaques in a Rat Model of Peyronie's Disease
Authors
Ghatak, KalyanNguyen Nhat MinhLimanjaya, AnitaKwon, Mi-HyeOck, JiyeonYin, Guo NanKim, Dae-KeeRyu, Ji-KanSuh, Jun-KyuSong, Kang-MoonChung, Doo YongChoi, Min Ji
Ewha Authors
김대기
SCOPUS Author ID
김대기scopus
Issue Date
2020
Journal Title
WORLD JOURNAL OF MENS HEALTH
ISSN
2287-4208JCR Link

2287-4690JCR Link
Citation
WORLD JOURNAL OF MENS HEALTH vol. 38, no. 4, pp. 552 - 563
Keywords
Activin receptorsFibrosisPeyronie's diseaseTransforming growth factor beta
Publisher
PUSAN NATL UNIV MEDICAL SCH, DEPT UROLOGY
Indexed
SCIE; KCI WOS
Document Type
Article
Abstract
Purpose: To examine the therapeutic effect of Vactosertib, a small molecule inhibitor of transforming growth factor-beta (TGF-beta) 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 mu L 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-1 beta-induced enhancement of extracellular matrix protein production and hydroxyproline content in PD fibroblasts in vitro by hindering the TGF-beta 1-induced Smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast transdifferentiation. Conclusions: In view of the critical role of TGB-beta 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.
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DOI
10.5534/wjmh.190071
Appears in Collections:
약학대학 > 약학과 > Journal papers
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