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Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie's disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation.

To uncover the anti-myofibroblast (MFB) properties of Rho-kinase inhibitor (compound Y-27632) and simvastatin in an in vitro model of Peyronie's disease (PD), a sexually debilitating disease caused by an irreversible fibrotic plaque in the penile tunica albuginea (TA).

Primary human fibroblasts (FBs) were isolated from surgically obtained TA tissue from patients with PD. To induce MFB status, cells were stimulated with 3 ng/mL transforming growth factor-β1 (TGF-β1). Increasing doses of Y-27632 and simvastatin were added. Real-time quantitative PCR was used to assess mRNA expression of α-smooth muscle actin (α-SMA), collagen III, elastin and connective tissue growth factor (CTGF) after 72 h. Western blot analysis was used to quantify α-SMA protein contents, and immunofluorescence (IF) was used to visualize MFB differentiation by staining for α-SMA after 72 h. A resazurin-based assay was used to assess cell viability to ensure the anti-MFB effect of the drugs. A mechanistic study was performed using IF staining for YAP/TAZ nuclear translocation.

After 72 h of stimulation with TGF-β1, a six- to 10-fold upregulation of α-SMA could be observed. When treated with Y-27632 or simvastatin, the α-SMA, collagen III, elastin and CTGF mRNA expression was impeded. Additionally, TGF-β1 stimulation showed a twofold increase in α-SMA protein expression, which was reversed to non-stimulated levels after treatment with Y-27632 and simvastatin. Using IF, stimulated cells were identified as MFB (α-SMA+, Vim+) as opposed to the non-stimulated, Y-27632- and simvastatin-treated cells (α-SMA-, Vim+). The resazurin-based assay confirmed that the cell viability was not compromised by the administered drugs. On stimulation with TGF-β1, nuclear translocation of YAP/TAZ could be observed, which was prevented by adding the aforementioned compounds.

Transformation of FBs into the contractile and extracellular matrix-producing MFBs occurs after TGF-β1 stimulation. In our experiments, Rho-kinase inhibition and simvastatin treatment were shown to prevent this in TGF-β1-stimulated cells on an RNA and protein level through the inhibition of YAP/TAZ nuclear translocation. Y-27632 and simvastatin could become a novel treatment option in the early treatment of PD.

BJU international. 2018 Dec 09 [Epub ahead of print]

Uros Milenkovic, Marcus M Ilg, Carola Zuccato, Yasaman Ramazani, Dirk De Ridder, Maarten Albersen

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium., Faculty of Health, Education, Medicine and Social Care, Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, UK., Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven and KU Leuven, Leuven, Belgium.

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