Silencing Histone Deacetylase 7 Alleviates Transforming Growth Factor-β1-Induced Profibrotic Responses in Fibroblasts Derived from Peyronie's Plaque

Abstract

PurposeEpigenetic modifications, such as histone acetylation/deacetylation and DNA methylation, play a crucial role in the pathogenesis of inflammatory disorders and fibrotic diseases. The aim of this study was to study the differential gene expression of histone deacetylases (HDACs) in fibroblasts isolated from plaque tissue of Peyronie's disease (PD) or normal tunica albuginea (TA) and to examine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of HDAC7 in fibroblasts derived from human PD plaque.Materials and MethodsFor differential gene expression study, we performed reverse-transcriptase polymerase chain reaction for HDAC isoforms (1–11) in fibroblasts isolated from PD plaque or normal TA. Fibroblasts isolated from PD plaque were pretreated with HDAC7 siRNA (100 pmol) and then stimulated with transforming growth factor-β1 (TGF-β1, 10 ng/mL). Protein was extracted from treated fibroblasts for Western blotting. 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 and myofibroblastic differentiation.ResultsThe mRNA expression of HDAC2, 3, 4, 5, 7, 8, 10, and 11 was higher in fibroblasts isolated from PD plaque than in fibroblasts isolated from normal TA tissue. Knockdown of HDAC7 in PD fibroblasts inhibited TGF-β1-induced nuclear shuttle of Smad2 and Smad3, transdifferentiation of fibroblasts into myofibroblasts, and abrogated TGF-β1-induced production of extracellular matrix protein.ConclusionsThese findings suggest that specific inhibition of HDAC7 with RNA interference may represent a promising epigenetic therapy for PD.

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

“…6A). Previous studies have identified HDAC7 as being a potential key player in fibrosis owing to TGFβ signaling upregulating its gene expression and its upregulation in fibroblastic foci in IPF lung tissue (Hemmatazad et al, 2009;Kang et al, 2018;Korfei et al, 2015), although functional studies have been lacking. Interestingly, we found that knockdown of HDAC7 in the presence of TGFβ also modestly reduced expression of HDAC8 (Fig.…”

New insights into the pathogenesis of Peyronie's disease: A narrative review

“…They also showed a decrease in myofibroblastic differentiation, and the phosphorylation of Smad2/3 in TGF-β1-induced fibroblasts derived from PD plaques. Kang et al 25 showed a similar effect by inhibiting histone deacetylase 7 with siRNA. They also demonstrated that the expression of mRNA of HDAC 2,3,4,5,7,8,10, and 11 isoforms was higher in fibroblasts derived from PD-plaque than in normal TA.…”

“…These factors include myofibroblast transformation from fibroblasts, fibrocytes of different origin, smooth muscle cells, MSC, and avoidance of apoptotic mechanisms. 19 , 25 Gabbiani et al originally described in 1971, that fibroblasts acquire smooth muscle cell features with the expression of desmin, caldesmon, and actin isoforms that aid progress of fibrotic events after injury, or during the development of granulation tissue. 71 Myofibroblasts generally participate in physiological wound healing by acting in tissue contraction and ECM secretion.…”

Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling

“…Similar to our observations in cultured cardiomyocytes, we find that the hearts of SIK1-null mice are depleted in HDAC7 protein, implicating that the SIK1/HDAC7 axis in cardiomyocytes is also operative in vivo. Silencing of HDAC7 has also been shown to inhibit myofibroblast differentiation (28), suggesting that SIK1 expression in fibroblasts may also contribute to heart failure pathogenesis. Although our current work establishes a role for SIKs in heart failure pathobiology, in the future it will be informative to annotate the role of SIK1 in other relevant cellular compartments that populate the stressed myocardium using a conditional gene-deletion approach.…”