Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cellsReport as inadecuate




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BMC Genomics

, 13:709

Human and rodent genomic

Abstract

BackgroundWe have shown previously that pan-HDAC inhibitors HDACIs m-carboxycinnamic acid bis-hydroxamide CBHA and trichostatin A TSA attenuated cardiac hypertrophy in BALB-c mice by inducing hyper-acetylation of cardiac chromatin that was accompanied by suppression of pro-inflammatory gene networks. However, it was not feasible to determine the precise contribution of the myocytes- and non-myocytes to HDACI-induced gene expression in the intact heart. Therefore, the current study was undertaken with a primary goal of elucidating temporal changes in the transcriptomes of cardiac myocytes exposed to CBHA and TSA.

ResultsWe incubated H9c2 cardiac myocytes in growth medium containing either of the two HDACIs for 6h and 24h and analyzed changes in gene expression using Illumina microarrays. H9c2 cells exposed to TSA for 6h and 24h led to differential expression of 468 and 231 genes, respectively. In contrast, cardiac myocytes incubated with CBHA for 6h and 24h elicited differential expression of 768 and 999 genes, respectively. We analyzed CBHA- and TSA-induced differentially expressed genes by Ingenuity Pathway IPA, Kyoto Encyclopedia of Genes and Genomes KEGG and Core TF programs and discovered that CBHA and TSA impinged on several common gene networks. Thus, both HDACIs induced a repertoire of signaling kinases PTEN-PI3K-AKT and MAPK and transcription factors Myc, p53, NFkB and HNF4A representing canonical TGF, TNF-, IFN and IL-6 specific networks. An overrepresentation of E2F, AP2, EGR1 and SP1 specific motifs was also found in the promoters of the differentially expressed genes. Apparently, TSA elicited predominantly TGF- and TNF--intensive gene networks regardless of the duration of treatment. In contrast, CBHA elicited TNF- and IFN specific networks at 6 h, followed by elicitation of IL-6 and IFN-centered gene networks at 24h.

ConclusionsOur data show that both CBHA and TSA induced similar, but not identical, time-dependent, gene networks in H9c2 cardiac myocytes. Initially, both HDACIs impinged on numerous genes associated with adipokine signaling, intracellular metabolism and energetics, and cell cycle. A continued exposure to either CBHA or TSA led to the emergence of a number of apoptosis- and inflammation-specific gene networks that were apparently suppressed by both HDACIs. Based on these data we posit that the anti-inflammatory and anti-proliferative actions of HDACIs are myocyte-intrinsic. These findings advance our understanding of the mechanisms of actions of HDACIs on cardiac myocytes and reveal potential signaling pathways that may be targeted therapeutically.

KeywordsHDAC-inhibitorInflammationCardiac gene expressionElectronic supplementary materialThe online version of this article doi:10.1186-1471-2164-13-709 contains supplementary material, which is available to authorized users.

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Author: GipsyMajumdar - PiyatilakeAdris - NehaBhargava - HaoChen - RajendraRaghow

Source: https://link.springer.com/







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