title: Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis.
abstract: Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-β1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-β signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. Electronic address: y-kawa@ior.twmu.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tochimoto
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katsumata
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Ichida
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hanaoka
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Kawasumi
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tochihara
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C526317:CCN2 protein, human; C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D058986:Phosphodiesterase 5 Inhibitors; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D000068677:Sildenafil Citrate; D006152:Cyclic GMP
keywords: CGMP; Fibrosis; Sildenafil; Systemic sclerosis