The Potential of Targeting Epigenetic Regulators for the Treatment of Fibrotic Cardiac Diseases

Schuetze, Katherine B.; Koch, Keith A.; McKinsey, Timothy A.

doi:10.4155/fmc-2016-0144

Cited by 2 publications

(1 citation statement)

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“…In this study, we evaluated whether administration of MS-275 (also known as entinostat), a selective inhibitor of class 1 histone deacetylases (HDACs), counteracts the development of pancreatic fibrosis using the widespread murine model of cerulein-induced chronic pancreatitis. The rationale for this approach was 3-fold: 1) development of fibrosis activates a substantial gene regulation, which is prominently orchestrated by epigenetic mechanisms (McDonnell et al, 2014;Weigel et al, 2015;Yang and Schwartz, 2015;Moran-Salvador and Mann, 2017); 2) HDACs are critical epigenetic regulators, and expression of class 1 HDACs is significantly upregulated during the course of chronic pancreatitis (Bombardo et al, 2017); and 3) pharmacologic inhibitors of HDAC activity, originally developed as anticancer agents, are currently being investigated for their antifibrotic properties in different fibrotic diseases (recently reviewed in Pang and Zhuang, 2010;Royce et al, 2014;Chen et al, 2015;Schuetze et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Class I Histone Deacetylases Abrogates Tumor Growth FactorβExpression and Development of Fibrosis during Chronic Pancreatitis

et al. 2018

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Pancreatic fibrosis is the hallmark of chronic pancreatitis, a highly debilitating disease for which there is currently no cure. The key event at the basis of pancreatic fibrosis is the deposition of extracellular matrix proteins by activated pancreatic stellate cells (PSCs). Transforming growth factor (TGF) is a potent profibrotic factor in the pancreas as it promotes the activation of PSC; thus, pharmacologic interventions that effectively reduce TGF expression harbor considerable therapeutic potential in the treatment of chronic pancreatitis. In this study, we investigated whether TGF expression is reduced by pharmacologic inhibition of the epigenetic modifiers histone deacetylases (HDACs). To address this aim, chronic pancreatitis was induced in C57BL/6 mice with serial injections of cerulein, and the selective class 1 HDAC inhibitor MS-275 was administered in vivo in a preventive and therapeutic manner. Both MS-275 regimens potently reduced deposition of extracellular matrix and development of fibrosis in the pancreas after 4 weeks of chronic pancreatitis. Reduced pancreatic fibrosis was concomitant with lower expression of pancreatic TGF and consequent reduced PSC activation. In search of the cell types targeted by the inhibitor, we found that MS-275 treatment abrogated the expression of TGF in acinar cells stimulated by cerulein treatment. Our study demonstrates that MS-275 is an effective antifibrotic agent in the context of experimental chronic pancreatitis and thus may constitute a valid therapeutic intervention for this severe disease.

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