S-Nitrosothiol Signaling Regulates Liver Development and Improves Outcome following Toxic Liver Injury
Andrew G. Cox,
Diane C. Saunders,
Peter B. Kelsey Jr.,
Allie A. Conway,
Yevgenia Tesmenitsky,
Julio F. Marchini,
Kristin K. Brown,
Jonathan S. Stamler,
Dorothy B. Colagiovanni,
Gary J. Rosenthal,
Kevin J. Croce,
Trista E. North,
Wolfram Goessling
Affiliations
Andrew G. Cox
Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Diane C. Saunders
Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Peter B. Kelsey Jr.
Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Allie A. Conway
Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Yevgenia Tesmenitsky
Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Julio F. Marchini
Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Kristin K. Brown
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Jonathan S. Stamler
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
Dorothy B. Colagiovanni
N30 Pharmaceuticals, Boulder, CO 80301, USA
Gary J. Rosenthal
N30 Pharmaceuticals, Boulder, CO 80301, USA
Kevin J. Croce
Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Trista E. North
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Wolfram Goessling
Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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.
