Sildenafil suppresses the activation of hypertrophic scar fibroblasts by promoting the KLF15-mediated inhibition of LOXL1 transcription

Hypertrophic scarring (HS) is a dermal fibroproliferative disorder accompanied by pain. Sildenafil (SIL) has been shown to have a protective effect against fibrosis. This study aimed to determine the effects and mechanisms of SIL on the proliferation, migration, and extracellular matrix (ECM) production of HS fibroblasts. The expression levels of Krüppel-like factor 15 (KLF15) and lysyl oxidase-like 1 (LOXL1) in human dermal fibroblasts (HDFbs) and HS-derived fibroblasts (HSFbs) were determined using reverse transcription-quantitative polymerase chain reaction and Western blotting. The effect of SIL on cell proliferation, migration, ECM production, and SMAD expression was assessed using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, transwell, and Western blotting assays, respectively. The effect of KLF15 on LOXL1 transcriptional activity was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Compared with HDFbs, HSFbs showed greater migration and ECM deposition. SIL inhibited cell proliferation, migration, ECM deposition, and SMAD activation in HSFbs, whereas these effects were inhibited by KLF15 knockdown. KLF15 inhibited LOXL1 transcription in HSFbs. LOXL1 silencing abrogated the effect of KLF15 knockdown on SIL-inhibited proliferation, migration, and ECM deposition. SIL inhibited the transcriptional activity of LOXL1 by upregulating KLF15, eventually inactivating SMAD signaling and suppressing the proliferation, migration, and ECM deposition of HSFbs.