TY - JOUR
T1 - Superoxide mediates acute liver injury in irradiated mice lacking Sirtuin 3
AU - Coleman, Mitchell C.
AU - Olivier, Alicia K.
AU - Jacobus, James A.
AU - Mapuskar, Kranti A.
AU - Mao, Gaowei
AU - Martin, Sean M.
AU - Riley, Dennis P.
AU - Gius, David
AU - Spitz, Douglas R.
PY - 2014/3/20
Y1 - 2014/3/20
N2 - Aims: This study determined whether acute radiation-induced liver injury seen in Sirtuin3-/- mice after exposure to Cs-137 γ-rays was mediated by superoxide anion (O2•-). Results: Male wild-type (WT) and SIRT3-/- mice were given 2×2 Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3-/- animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3 -/- animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2 mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30 min before each fraction. Innovation: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O2 •- in the liver injury process initiated by whole-body irradiation in SIRT3-/- mice. Conclusion: These results support the hypothesis that O2•- mediates acute liver injury in SIRT3-/- animals exposed to whole-body γ-radiation and suggest that GC4401 could be used as a radio-protective compound in vivo. Antioxid.
AB - Aims: This study determined whether acute radiation-induced liver injury seen in Sirtuin3-/- mice after exposure to Cs-137 γ-rays was mediated by superoxide anion (O2•-). Results: Male wild-type (WT) and SIRT3-/- mice were given 2×2 Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3-/- animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3 -/- animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2 mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30 min before each fraction. Innovation: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O2 •- in the liver injury process initiated by whole-body irradiation in SIRT3-/- mice. Conclusion: These results support the hypothesis that O2•- mediates acute liver injury in SIRT3-/- animals exposed to whole-body γ-radiation and suggest that GC4401 could be used as a radio-protective compound in vivo. Antioxid.
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U2 - 10.1089/ars.2012.5091
DO - 10.1089/ars.2012.5091
M3 - Article
C2 - 23919724
AN - SCOPUS:84895484416
SN - 1523-0864
VL - 20
SP - 1423
EP - 1435
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 9
ER -