Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency
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ABSTRACT: Rationale: Myocardial fibrosis manifests progressively in several forms of cardiomyopathies. Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. Objective: The anthraquinone Rhein, a compound from rhubarb, was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Methods and Results: Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent acetylation status of p53 a posttranslational modification that acts protein stabilizing. Direct enzymatic testing revealed an inhibitory potency of Rhein for HDAC classes I/II. Functionally, Rhein inhibited collagen contraction in response to protein abundance of SMAD7, endogenous inhibitor of TGFβ1 action, thus demonstrating its anti-fibrotic property in cardiac remodeling. Conclusion: In conclusion, this study identifies Rhein as a novel potent HDAC inhibitor and provides evidence that Rhein may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.
ORGANISM(S): Homo sapiens
PROVIDER: GSE136039 | GEO | 2020/04/17
REPOSITORIES: GEO
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