title: Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque.
abstract: Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-β1 (TGF-β1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle α-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-β1-induced extracellular matrix production by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.forename: Woo-Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Jin-Mi
authors.initials: JM
authors.lastname: Park
authors.forename: Kang-Moon
authors.initials: KM
authors.lastname: Song
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Nando-Dulal
authors.initials: ND
authors.lastname: Das
authors.forename: Ki-Dong
authors.initials: KD
authors.lastname: Kwon
authors.forename: Dulguun
authors.initials: D
authors.lastname: Batbold
authors.forename: Guo-Nan
authors.initials: GN
authors.lastname: Yin
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008297:Male; D010411:Penile Induration / Q000473:pathology / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D056464:Histone Deacetylase 2