title: Histone deacetylase-3 activation promotes tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes during lipopolysaccharide stimulation.
abstract: Lipopolysaccharides (LPS) induce tumor necrosis factor-alpha (TNF-alpha) production in cardiomyocytes, which contributes to myocardial depression during sepsis. However, the underlying mechanisms remain not fully understood. This study was undertaken to investigate the contribution of histone deacetylase (HDAC) to TNF-alpha expression in cardiomyocytes and the signaling mechanism of LPS-induced HDAC activation. Here, we show for the first time that LPS increases HDAC activity and that inhibition of HDAC decreases LPS-stimulated TNF-alpha expression via the accumulation of NF-kappaB/p65 at the TNF-alpha promoter in cardiomyocytes. Using a positive screen, we have further identified HDAC3 as a specific member of the HDAC family able to regulate TNF-alpha production. Furthermore, our data reveal that LPS-induced HDAC activity is mediated through reactive oxygen species from mitochondria and c-Src signaling. In summary, this study demonstrates a novel signaling mechanism by which LPS via mitochondrial reactive oxygen species/c-Src/HDAC3 pathways mediate TNF-alpha expression in cardiomyocytes.
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada; Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei 230032, China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada.
authors.forename: Limei
authors.initials: L
authors.lastname: Shan
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Istituto Pasteur, Fondazione Cenci-Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco "Sapienza," Università di Roma, I-00185 Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada; Pathology, University of Western Ontario, London, Ontario N6A 4G5, Canada. Electronic address: tpeng2@uwo.ca.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D006655:Histone Deacetylases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019061:src-Family Kinases; D000099186:Histone Deacetylase 3
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D006655:Histone Deacetylases; D008070:Lipopolysaccharides; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D000099186:Histone Deacetylase 3