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

Abstract

ObjectivesTo uncover the anti-myofibroblast (MFB) properties of Rhokinase 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). ConclusionTransformation of FBs into the contractile and extracellular matrix-producing MFBs occurs after TGF-b1 stimulation. In our experiments, Rho-kinase inhibition and simvastatin treatment were shown to prevent this in TGF-b1-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.

Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves’ Ophthalmopathy-Derived Orbital Fibroblasts via RhoA-Mediated ERK and p38 Signaling Pathways

“…Some studies have demonstrated the inhibitory effects of simvastatin and Y-27632 on TGF-b-induced myofibroblast differentiation from fibroblasts derived from different disease specimens, such as nasal polyps (24), keloids (20), and penile tunica albuginea from Peyronie's disease (21). To the best of our knowledge, this is the first study to investigate the antifibrotic effects of simvastatin and Y-27632 in GO-derived fibroblasts.…”

“…Statins inhibit the synthesis of intermediates of cholesterol biosynthesis such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are essential for the post-translational modification of the Rho family proteins (8). Therefore, statins have a potential therapeutic role in fibrotic diseases owing to their inhibitory effects on RhoA/ROCK signaling (20,21). Simvastatin, a type of statin, can suppress TGF-b-induced myofibroblast transformation of fibroblasts through RhoA/ROCK inhibition (20,21).…”

“…Therefore, statins have a potential therapeutic role in fibrotic diseases owing to their inhibitory effects on RhoA/ROCK signaling (20,21). Simvastatin, a type of statin, can suppress TGF-b-induced myofibroblast transformation of fibroblasts through RhoA/ROCK inhibition (20,21).…”

Molecular Mechanisms and Current Pharmacotherapy of Peyronie’s Disease: A Review

“…On the other hand, it is reported that TGFβ1 is a possible driver of Rho-associated coiled-coil protein kinase (ROCK) ( Milenkovic et al, 2019d ). Activation and up-regulation of ROCK have been examined in the corpora cavernosa following neuropraxia ( Sezen et al, 2014 ).…”

“…Meanwhile, Rho/RhoA signaling works partly through nuclear translocation of YAP/TAZ ( Knipe et al, 2015 ). Y-27632, a ROCK inhibitor, coupled with simvastatin has been shown to suppress the TGF-β1-induced myofibroblast transformation by prevention of YAP/TAZ nuclear translocation ( Milenkovic et al, 2019d ). In this respect, the inhibition of YAP/TAZ nuclear translocation might have anti-fibrotic effects, providing a novel target for PD.…”