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Cell Rep. 2014 Jan 16;6(1):56-69. doi: 10.1016/j.celrep.2013.12.007. Epub 2014 Jan 2.

S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.

Author information

1
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
4
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.
5
N30 Pharmaceuticals, Boulder, CO 80301, USA.
6
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.
7
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.

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.

PMID:
24388745
PMCID:
PMC4008725
DOI:
10.1016/j.celrep.2013.12.007
[Indexed for MEDLINE]
Free PMC Article

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