Ionizing Radiation Accelerates Aortic Lesion Formation in Fat-Fed Mice via SOD-Inhibitable Processes

Abstract

Abstract —Ionizing radiation promotes formation of reactive oxygen species, including the superoxide anion (O 2 − ). To evaluate whether O 2 − or O 2 − -mediated perturbations may contribute to the known atherogenic effects of radiation, we examined aortic lesion formation in irradiated C57BL/6 mice and evaluated the effects of CuZn-superoxide dismutase (CuZn-SOD) overexpression. Ten-week-old mice were exposed to a 2-, 4-, or 8-Gy dose of 250-keV x-rays to the upper thorax and then placed on a high-fat diet for 18 weeks. Based on quantitative lipid staining of serial sections of the proximal aorta, mean lesion area was increased with increasing radiation dose and was 3-fold greater in 8-Gy–irradiated than sham-irradiated mice (7800±2140 versus 2635±709 μm 2 , P <0.05). These effects were absolutely dependent on a high-fat diet, which had to be introduced within 1 to 2 weeks of the radiation exposure, suggesting the early involvement of atherogenic lipoproteins that were elevated in response to the diet. The importance of radiation-induced oxidative stress was supported by the observation of a 2-fold lower mean lesion area in irradiated CuZn-SOD transgenic mice than in their irradiated, nontransgenic littermates (3026±1590 versus 6102±1834 μm 2 , P <0.05). Lucigenin-enhanced chemiluminescence, used as an index of aortic O 2 − concentrations, was significantly elevated in the postradiation period, and this response was reduced in CuZn-SOD transgenics. On the basis of these results, we propose that radiation may be a useful tool for initiating oxidative or redox-regulated events that promote atherogenesis and for testing the antiatherogenic properties of antioxidants.