title: Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter.
abstract: Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5'UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1-silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS.
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Venkateswaran Ramamoorthi
authors.initials: VR
authors.lastname: Elangovan
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Camp
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Gabriel T
authors.initials: GT
authors.lastname: Kelly
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Djanybek
authors.initials: D
authors.lastname: Adyshev
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
keywords: DNA methylation; epigenetic modifiers; epigenetics; histone acetylation; lung endothelium