Mirodenafil ameliorates skin fibrosis in bleomycin-induced mouse model of systemic sclerosis

• Published in: Animal cells and systems Vol. 25; no. 6; pp. 387 - 395
• Main Authors: Roh, Jong Seong, Jeong, Hoim, Lee, Beomgu, Song, Byung Wook, Han, Seung Jin, Sohn, Dong Hyun, Lee, Seung-Geun
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.11.2021; Taylor & Francis Ltd; Taylor & Francis Group; 한국통합생물학회
• Subjects: Autoimmune diseases; Bleomycin; Collagen; Collagen (type I); cyclic guanosine monophosphate; Embryo fibroblasts; Fibroblasts; Fibrosis; Gene expression; Genes; Growth factors; mirodenafil; Organs; Pathogenesis; Phosphodiesterase; Phosphorylation; Scleroderma; Signal transduction; Smad protein; Smad2 protein; Systemic sclerosis; 생물학; cyclic guanosine monophosphate; mirodenafil; systemic sclerosis; Fibrosis
• ISSN: 1976-8354; 2151-2485
• DOI: 10.1080/19768354.2021.1995486

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Despite the recent advances in the pathogenesis and treatment of SSc, effective therapies for fibrosis caused by SSc have not yet been established. In this study, we investigated the potential role of mirodenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, in the treatment of fibrosis in SSc. We used a bleomycin (BLM)-induced SSc mouse model to mimic the typical features of fibrosis in human SSc and examined the dermal thickness to assess the degree of skin fibrosis after staining with hematoxylin and eosin or Masson's trichrome stains. The effect of mirodenafil on the expression of profibrotic genes was also analyzed by treating fibroblasts with transforming growth factor (TGF)-β and mirodenafil. We showed that mirodenafil ameliorated dermal fibrosis and downregulated the protein levels of fibrosis markers including COL1A1 and α-SMA in the BLM-induced SSc mouse model. Further, using mouse embryonic fibroblasts and human lung fibroblasts, we demonstrated that the expression of collagen and profibrotic genes was reduced by treatment with mirodenafil. Finally, we showed that mirodenafil inhibited TGF-β-induced phosphorylation of Smad2/3 in fibroblasts, which suggested that this drug may ameliorate fibrosis by suppressing the TGF-β/Smad signaling pathway. Our findings suggest that mirodenafil possesses a therapeutic potential for treating fibrosis in SSc.