Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter.

TitleEndotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter.
Publication TypeJournal Article
Year of Publication2016
AuthorsElangovan VRamamoorth, Camp SM, Kelly GT, Desai AA, Adyshev D, Sun X, Black SM, Wang T, Garcia JGN
JournalPulm Circ
Volume6
Issue4
Pagination539-544
Date Published2016 Dec
ISSN Number2045-8932
Abstract

<p>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.</p>

DOI10.1086/688761
Alternate JournalPulm Circ
PubMed ID28090296
PubMed Central IDPMC5210063
Grant ListP01 HL101902 / HL / NHLBI NIH HHS / United States
R01 HL060190 / HL / NHLBI NIH HHS / United States
R01 HL067841 / HL / NHLBI NIH HHS / United States
R01 HL136603 / HL / NHLBI NIH HHS / United States