title: Panhistone deacetylase inhibitors inhibit proinflammatory signaling pathways to ameliorate interleukin-18-induced cardiac hypertrophy.
abstract: We investigated the genome-wide consequences of pan-histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and m-carboxycinnamic acid bis-hydroxamide (CBHA) in the hearts of BALB/c mice eliciting hypertrophy in response to interleukin-18 (IL-18). Both TSA and CBHA profoundly altered cardiac chromatin structure that occurred concomitantly with normalization of IL-18-induced gene expression and amelioration of cardiac hypertrophy. The hearts of mice exposed to IL-18+/-TSA or CBHA elicited distinct gene expression profiles. Of 184 genes that were differentially regulated by IL-18 and TSA, 33 were regulated in an opposite manner. The hearts of mice treated with IL-18 and/or CBHA elicited 147 differentially expressed genes (DEGs), a third of which were oppositely regulated by IL-18 and CBHA. Ingenuity Pathways and Kyoto Encyclopedia of Genes and Genomes analyses of DEGs showed that IL-18 impinged on TNF-α- and IFNγ-specific gene networks relegated to controlling immunity and inflammation, cardiac metabolism and energetics, and cell proliferation and apoptosis. These TNF-α- and IFNγ-specific gene networks, extensively connected with PI3K, MAPK, and NF-κB signaling pathways, were oppositely regulated by IL-18 and pan-HDACIs. Evidently, both TSA and CBHA caused a two- to fourfold induction of phosphatase and tensin homolog expression to counteract IL-18-induced proinflammatory signaling and cardiac hypertrophy.
authors.affiliation: Department of Veterans Affairs Medical Center, University of Tennessee Health Science Center, Memphis, TN 38104, USA.
authors.forename: Gipsy
authors.initials: G
authors.lastname: Majumdar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rooney
authors.forename: I Maria
authors.initials: IM
authors.lastname: Johnson
authors.forename: Rajendra
authors.initials: R
authors.lastname: Raghow
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D020382:Interleukin-18 / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D020382:Interleukin-18; C111238:carboxycinnamic acid bishydroxamide; C012589:trichostatin A