Glutathione S-transferase alpha 4 (GSTA4-4) is one of the enzymes responsible for the removal of 4-hydroxynonenal (4-HNE), an electrophilic product of lipid peroxidation in cellular membranes during oxidative stress. 4-HNE is a direct activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor with many target genes encoding antioxidant and anti-electrophile enzymes. We have previously shown that Gsta4-null mice on a 129/Sv background exhibited increased activity of Nrf2 in the heart. Here we examined the sensitivity of this Gsta4-null mouse model towards cardiac function and structure loss due to local heart irradiation. Male Gsta4-null and wild-type mice were exposed to a single X-ray dose of 18 Gy to the heart. Six months after irradiation, immunohistochemical staining for respiratory complexes 2 and 5 indicated that radiation exposure had caused most pronounced alterations in mitochondrial morphology in Gsta4-null mice. On the other hand, wild-type mice showed a decline in cardiac function and an increase in plasma levels of troponin-I, while no such changes were observed in Gsta4-null mice. Radiation-induced Nrf2-target gene expression only in Gsta4-null mice. In conclusion, although loss of GSTA4-4 led to enhanced susceptibility of cardiac mitochondria to radiation-induced loss of morphology, cardiac function was preserved in Gsta4-null mice. We propose that this protection against cardiac function loss may occur, at least in part, by upregulation of the Nrf2 pathway.
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1 June 2015
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May 26 2015
Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model
Marjan Boerma;
Marjan Boerma
,1
Departments ofa Pharmaceutical Sciences, Division of Radiation Health,
1 Address for correspondence: University of Arkansas for Medical Sciences, Department of Pharmaceutical Sciences, 4301 West Markham, Slot 522-10, Little Rock, AR 72205; e-mail: mboerma@uams.edu.
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Preeti Singh;
Preeti Singh
b Pharmacology and Toxicology and
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Vijayalakshmi Sridharan;
Vijayalakshmi Sridharan
Departments ofa Pharmaceutical Sciences, Division of Radiation Health,
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Preeti Tripathi;
Preeti Tripathi
Departments ofa Pharmaceutical Sciences, Division of Radiation Health,
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Sunil Sharma;
Sunil Sharma
c Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Sharda P. Singh
Sharda P. Singh
b Pharmacology and Toxicology and
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Radiat Res (2015) 183 (6): 610–619.
Article history
Received:
November 26 2014
Accepted:
March 09 2015
Citation
Marjan Boerma, Preeti Singh, Vijayalakshmi Sridharan, Preeti Tripathi, Sunil Sharma, Sharda P. Singh; Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model. Radiat Res 1 June 2015; 183 (6): 610–619. doi: https://doi.org/10.1667/RR13979.1
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