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.

Effects of ionizing radiation on the heart

“…Radiation-induced heart disease in animal models appears to be associated with long-term oxidative stress [36;43;46]. Hence, some of the interventions that have been tested in animal models of radiation-induced heart disease act via anti-oxidant mechanisms.…”

“…These relatively low α/β ratios are typical for late radiation responding organs and, as described above, suggest that cardiac injury is dependent on dose per fraction. However, most research into mechanisms by which radiation modifies the heart has been performed mostly with a high-dose rate single high dose of radiation to the heart, or a limited number of fractions [43–46]. While these radiation protocols seem to cause comparable late cardiac remodeling, there is insufficient data available from animal models to determine whether fractionation schedules as used in the clinic cause cardiovascular effects similar to single high-dose exposures.…”

“…Single dose local heart irradiation in rodent models causes long-term alterations in the function, morphology, and protein expression of cardiac mitochondria [43;61–63]. Sequestered on the mitochondrial membrane in its inactive form is nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), a transcription factor that regulates the expression of various anti-oxidant enzymes [64].…”

“…Sequestered on the mitochondrial membrane in its inactive form is nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), a transcription factor that regulates the expression of various anti-oxidant enzymes [64]. While the Nrf2 pathway is linked to reduced radiation injury in several organs including the heart [43;65–67], the exact role of mitochondrial alterations and the Nrf2 pathway in radiation-induced heart disease has not yet been determined.…”

“…Local heart irradiation in rodent models (15–21 Gy single dose or 5 daily fractions of 9 Gy) leads to an increase in cardiac mast cell numbers that coincide with the development of radiation fibrosis [43;47]. However, contrary to what may be expected, experiments in a mast cell-deficient rat model suggest that mast cells play a predominantly protective role in radiation-induced heart disease [68].…”