title: Histone acetylation regulates the cell-specific and interferon-γ-inducible expression of extracellular superoxide dismutase in human pulmonary arteries.
abstract: Extracellular superoxide dismutase (EC-SOD) is the major antioxidant enzyme present in the vascular wall, and is responsible for both the protection of vessels from oxidative stress and for the modulation of vascular tone. Concentrations of EC-SOD in human pulmonary arteries are very high relative to other tissues, and the expression of EC-SOD appears highly restricted to smooth muscle. The molecular basis for this smooth muscle-specific expression of EC-SOD is not known. Here we assessed the role of epigenetic factors in regulating the cell-specific and IFN-γ-inducible expression of EC-SOD in human pulmonary artery cells. The analysis of CpG site methylation within the promoter and coding regions of the EC-SOD gene demonstrated higher levels of DNA methylation within the distal promoter region in endothelial cells compared with smooth muscle cells. Exposure of both cell types to DNA demethylation agents reactivated the transcription of EC-SOD in endothelial cells alone. However, exposure to the histone deacetylase inhibitor trichostatin A (TSA) significantly induced EC-SOD gene expression in both endothelial cells and smooth muscle cells. Concentrations of EC-SOD mRNA were also induced up to 45-fold by IFN-γ in smooth muscle cells, but not in endothelial cells. The IFN-γ-dependent expression of EC-SOD was regulated by the Janus tyrosine kinase/signal transducers and activators of transcription proteins signaling pathway. Simultaneous exposure to TSA and IFN-γ produced a synergistic effect on the induction of EC-SOD gene expression, but only in endothelial cells. These findings provide strong evidence that EC-SOD cell-specific and IFN-γ-inducible expression in pulmonary artery cells is regulated, to a major degree, by epigenetic mechanisms that include histone acetylation and DNA methylation.
authors.affiliation: Department of Medicine, University of Louisville, KY 40202, USA. igor.zelko@louisville.edu
authors.forename: Igor N
authors.initials: IN
authors.lastname: Zelko
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Stepp
authors.forename: Alan L
authors.initials: AL
authors.lastname: Vorst
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Folz
mesh_terms: D000107:Acetylation; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011651:Pulmonary Artery / Q000201:enzymology*; D050791:STAT Transcription Factors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D050791:STAT Transcription Factors; C012589:trichostatin A; D007371:Interferon-gamma; D013482:Superoxide Dismutase; D053612:Janus Kinases