title: S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.
abstract: Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cox
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Saunders
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kelsey
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Allie A
authors.initials: AA
authors.lastname: Conway
authors.affiliation: Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yevgenia
authors.initials: Y
authors.lastname: Tesmenitsky
authors.affiliation: Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Julio F
authors.initials: JF
authors.lastname: Marchini
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Institute for Transformative Molecular Medicine and Department of Medicine, Harrington Discovery Institute, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.affiliation: N30 Pharmaceuticals, Boulder, CO 80301, USA.
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Colagiovanni
authors.affiliation: N30 Pharmaceuticals, Boulder, CO 80301, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
authors.affiliation: Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Croce
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: wgoessling@partners.org.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D026403:S-Nitrosothiols / Q000494:pharmacology* / Q000627:therapeutic use; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D020030:Nitric Oxide Donors; D026403:S-Nitrosothiols; D029961:Zebrafish Proteins; C495638:nfe2l2a protein, zebrafish; D009569:Nitric Oxide; D000082:Acetaminophen; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent