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Schuetze KB , Stratton MS , Blakeslee WW , Wempe MF , Wagner FF , Holson EB , Kuo YM , Andrews AJ , Gilbert TM , Hooker JM , McKinsey TA
Overlapping and Divergent Actions of Structurally Distinct HDAC Inhibitors in Cardiac Fibroblasts
J Pharmacol Exp Ther. 2017 Apr;361(1) :140-150
PMID: 28174211    PMCID: PMC5363768    URL: https://www.ncbi.nlm.nih.gov/pubmed/28174211
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Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly impact cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiological and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103, was shown to block cardiac fibrosis, a process involving excess extracellular matrix (ECM) deposition, which often results in heart dysfunction. Here, we compare the mechanisms of action of structurally distinct HDAC inhibitors in isolated primary cardiac fibroblasts, which are the major ECM-producing cells of the heart. TSA, MGCD0103, and the cyclic peptide class I HDAC inhibitor, apicidin, exhibited a common ability to enhance histone acetylation, and all potently blocked cardiac fibroblast cell cycle progression. In contrast, MGCD0103, but not TSA or apicidin, paradoxically increased expression of a subset of fibrosis-associated genes. Using the cellular thermal shift assay (CETSA), we provide evidence that the divergent effects of the HDAC inhibitors on cardiac fibroblast gene expression relates to differential engagement of HDAC1 and HDAC2-containing complexes. These findings illustrate the importance of employing multiple compounds when pharmacologically assessing HDAC function in a cellular context, and during HDAC inhibitor drug development.
1521-0103 Schuetze, Katherine B Stratton, Matthew S Blakeslee, Weston W Wempe, Michael F Wagner, Florence F Holson, Edward B Kuo, Yin-Ming Andrews, Andrew J Gilbert, Tonya M Hooker, Jacob M McKinsey, Timothy A R01 HL116848/HL/NHLBI NIH HHS/United States R01 HL127240/HL/NHLBI NIH HHS/United States R21 AG043822/AG/NIA NIH HHS/United States Journal Article United States J Pharmacol Exp Ther. 2017 Feb 7. pii: jpet.116.237701. doi: 10.1124/jpet.116.237701.