Increased low density lipoprotein degradation in aorta of irradiated mice is inhibited by preenrichment of low density lipoprotein with alpha-tocopherol

We previously reported that upper thoracic exposure to ionizing radiation ( IR) accelerates fatty streak formation in C57BL/6 mice and that such effect s are inhibited by overexpression of the antioxidant enzyme CuZn-superoxide dismutase (SOD), Notably, ZR-accelerated lesion formation is strictly depe ndent on a high fat diet (i.e., atherogenic lipoproteins) but does not invo lve alterations in circulating lipid or lipoprotein levels. We thus propose d that LR promotes changes in the artery wall that enhance the deposition o f lipoprotein lipids. To address this hypothesis, we examined the effects o f IR on aortic accumulation and degradation of low density lipoproteins (LD L). Ten-week-old C57BL/6 mice were exposed to a single (8-Gy) dose of Co-60 radiation to the upper thoracic area or were sham irradiated (controls) an d were then placed on the high fat diet. Five days postexposure, the mice r eceived either I-125-labeled LDL (I-125-LDL) (which was used to measure int act LDL) or I-125-labeled tyramine cellobiose (I-125-TC)-LDL (which was use d to measure both intact and cell-degraded LDL) via tail vein injection. On the basis of trichloroacetic acid (TCA)-precipitable counts in retroorbita l blood samples, greater than or equal to 95% of donor LDL was cleared with in 24 h and there were no differences in time-averaged plasma concentration s of the two forms of LDL among irradiated and control mice. Aortic values increased markedly within the first hour and thereafter exhibited a slow in crease up to 24 h. There were no differences between irradiated and control mice at 1 h, when values primarily reflected LDL entry, but a divergence w as observed thereafter. At 24 h, I-125-TC-associated counts were 1.8-fold h igher in irradiated mice (P = 0.10). In contrast, I-125-LDI-associated coun ts were 30% lower in irradiated mice (P < 0.05), suggesting that most of th e retained I-125-TC was associated with LDL degradation products. Consisten t with the proposed involvement of oxidative or redox-regulated events, IR- induced LDL degradation was lower in SOD-transgenic than wild-type mice (P < 0.05). The importance of LDL oxidation was suggested by observations that IR-induced LDL degradation was significantly reduced by preenriching LDL w ith alpha-tocopherol. On the basis of these results, we propose that IR eli cits SOD-inhibitable changes in the artery wall that enhance LDL oxidation and degradation leading to the deposition of LDL-borne lipids. These studie s provide additional support for the role of oxidation in lipoprotein lipid deposition and atherogenesis and suggest that IR promotes an arterial envi ronment that stimulates this process in vivo.