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 effects are inhibited by overexpression of the antioxidant enzyme CuZn-superoxide dismutase (SOD). Notably, IR-accelerated lesion formation is strictly dependent on a high fat diet (i.e., atherogenic lipoproteins) but does not involve alterations in circulating lipid or lipoprotein levels. We thus proposed that IR promotes changes in the artery wall that enhance the deposition of lipoprotein lipids. To address this hypothesis, we examined the effects of IR on aortic accumulation and degradation of low density lipoproteins (LDL). Ten-week-old C57BL/6 mice were exposed to a single (8-Gy) dose of (60)Co radiation to the upper thoracic area or were sham irradiated (controls) and were then placed on the high fat diet. Five days postexposure, the mice received either (125)I-labeled LDL ((125)I-LDL) (which was used to measure intact LDL) or (125)I-labeled tyramine cellobiose ((125)I-TC)-LDL (which was used to measure both intact and cell-degraded LDL) via tail vein injection. On the basis of trichloroacetic acid (TCA)-precipitable counts in retroorbital blood samples, > or =95% of donor LDL was cleared within 24 h and there were no differences in time-averaged plasma concentrations of the two forms of LDL among irradiated and control mice. Aortic values increased markedly within the first hour and thereafter exhibited a slow increase 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 was observed thereafter. At 24 h, (125)I-TC-associated counts were 1.8-fold higher in irradiated mice (P = 0.10). In contrast, (125)I-LDL-associated counts were 30% lower in irradiated mice (P< 0.05), suggesting that most of the retained (125)I-TC was associated with LDL degradation products. Consistent 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 with alpha-tocopherol. On the basis of these results, we propose that IR elicits SOD-inhibitable changes in the artery wall that enhance LDL oxidation and degradation leading to the deposition of LDL-borne lipids. These studies provide additional support for the role of oxidation in lipoprotein lipid deposition and atherogenesis and suggest that IR promotes an arterial environment that stimulates this process in vivo.
Tribble
D L
DL
Life Science Division, Department of Molecular and Nuclear Medicine, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA.
Krauss
R M
RM
Chu
B M
BM
Gong
E L
EL
Kullgren
B R
BR
Nagy
J O
JO
La Belle
M
M
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000528:radiation effects*; D001161:Arteriosclerosis / Q000517:prevention & control; D002475:Cellobiose / Q000378:metabolism / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D014439:Tyramine / Q000378:metabolism / Q000493:pharmacokinetics; D014810:Vitamin E / Q000494:pharmacology*
D016166:Free Radical Scavengers; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; C038394:tyramine-cellobiose adduct; D014810:Vitamin E; D002475:Cellobiose; D013482:Superoxide Dismutase; D014439:Tyramine