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

J Pharmacol Exp Ther
Authors
Keywords
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.

Year of Publication
2017
Journal
J Pharmacol Exp Ther
Volume
361
Issue
1
Pages
140-150
Date Published
2017 Apr
ISSN
1521-0103
DOI
10.1124/jpet.116.237701
PubMed ID
28174211
PubMed Central ID
PMC5363768
Links
Grant list
R01 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