TY - JOUR T1 - Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 480 LP - 486 DO - 10.1124/jpet.114.213520 VL - 349 IS - 3 AU - Andrew J. Haak AU - Pei-Suen Tsou AU - Mohammad A. Amin AU - Jeffrey H. Ruth AU - Phillip Campbell AU - David A. Fox AU - Dinesh Khanna AU - Scott D. Larsen AU - Richard R. Neubig Y1 - 2014/06/01 UR - http://jpet.aspetjournals.org/content/349/3/480.abstract N2 - Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)–and serum response factor (SRF)–regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)–and transforming growth factor β (TGFβ)–stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders. ER -