title: Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model.
abstract: 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.
authors.affiliation: Departments of a  Pharmaceutical Sciences, Division of Radiation Health.
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
authors.affiliation: b  Pharmacology and Toxicology and.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Departments of a  Pharmaceutical Sciences, Division of Radiation Health.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Sridharan
authors.affiliation: Departments of a  Pharmaceutical Sciences, Division of Radiation Health.
authors.forename: Preeti
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: c  Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: b  Pharmacology and Toxicology and.
authors.forename: Sharda P
authors.initials: SP
authors.lastname: Singh
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000172:deficiency* / Q000235:genetics*; D006321:Heart / Q000502:physiology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D010100:Oxygen / Q000378:metabolism; D019210:Troponin I / Q000097:blood
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D019210:Troponin I; C529117:GSTA4-4 protein, mouse; D005982:Glutathione Transferase; D010100:Oxygen