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J Pharmacol Exp Ther DOI:10.1124/jpet.116.237701

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts.

Publication TypeJournal Article
Year of Publication2017
AuthorsSchuetze, KB, Stratton, MS, Blakeslee, WW, Wempe, MF, Wagner, FF, Holson, EB, Kuo, Y-M, Andrews, AJ, Gilbert, TM, Hooker, JM, McKinsey, TA
JournalJ Pharmacol Exp Ther
Volume361
Issue1
Pages140-150
Date Published2017 Apr
ISSN1521-0103
KeywordsAnimals, Animals, Newborn, Cells, Cultured, Fibroblasts, Histone Deacetylase 1, Histone Deacetylase Inhibitors, Mice, Mice, Inbred C57BL, Myocytes, Cardiac, Rats, Rats, Sprague-Dawley
Abstract

Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect 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 physiologic and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103 [N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide], was shown to block cardiac fibrosis, a process involving excess extracellular matrix 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 extracellular matrix-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, we provide evidence that the divergent effects of HDAC inhibitors on cardiac fibroblast gene expression relate 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.

DOI10.1124/jpet.116.237701
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28174211?dopt=Abstract

Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID28174211
PubMed Central IDPMC5363768
Grant ListR01 HL116848 / HL / NHLBI NIH HHS / United States
R01 HL127240 / HL / NHLBI NIH HHS / United States
T32 HL007822 / HL / NHLBI NIH HHS / United States
R01 GM102503 / GM / NIGMS NIH HHS / United States
R21 AG043822 / AG / NIA NIH HHS / United States
F32 HL126354 / HL / NHLBI NIH HHS / United States
T32 GM007635 / GM / NIGMS NIH HHS / United States