title: Fatty streak formation in fat-fed mice expressing human copper-zinc superoxide dismutase.
abstract: Studies in vitro have shown that copper-zinc superoxide dismutase (CuZn-SOD) inhibits a number of events putatively involved in atherogenesis, including cell-mediated oxidation of LDL. To investigate whether increased activity of CuZn-SOD reduces atherogenesis in vivo, we examined diet-induced fatty streak formation in CuZn-SOD transgenic mice (n = 24) as compared with their nontransgenic littermates (n = 28). Transgenic animals were originally created by introduction of an EcoRI-BamHI human genomic DNA fragment containing the CuZn-SOD gene and its regulatory elements into B6SJL zygotes. For the current studies, the transgene was bred for 12 generations into the atherosclerosis-susceptible C57BL/6 background. Animals were fed atherogenic diets (15% fat, 1.25% cholesterol, 0.5% Na cholate) starting at 100 weeks of age and extending for 18 weeks. At the end of the diet period, aortic SOD activity was two-fold higher in transgenics than nontransgenics (mean +/- SE: 46.7 +/- 5.8 versus 20.1 +/- 2.4 units/mg of protein, P < .001). Levels of protein-bound amino acid oxidation products (meta-, ortho-, and dityrosine) were either similar or lower in aorta and heart from transgenics as compared with nontransgenics, suggesting that amplification of CuZn-SOD activity above the normal complement had modest inhibitory effects on basal oxidative stress in these tissues. CuZn-SOD overexpression did not reduce the extent of lesion development as analyzed by quantitative lipid staining of serial sections of the proximal aorta; mean lesion areas (+/- SE) were 997 +/- 478 and 943 +/- 221 mu 2 in transgenics and nontransgenics, respectively. Notably, the range of values for lesion area was 2.2-fold greater in transgenics (0-8403 versus 0-3868 mu 2 in nontransgenics). Moreover, within this group, lesion area showed a significant positive correlation with SOD activity (r = .611, P < .03). These results do not support an antiatherogenic effect of Cu-Zn-SOD over expression and raise the possibility that high tissue SOD activity may potentiate atherogenesis in fat-fed atherosclerosis-susceptible mice [corrected].
authors.affiliation: Department of Molecular and Nuclear Medicine, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Tribble
authors.forename: E L
authors.initials: EL
authors.lastname: Gong
authors.forename: C
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: J W
authors.initials: JW
authors.lastname: Heinecke
authors.forename: E L
authors.initials: EL
authors.lastname: Carlson
authors.forename: J G
authors.initials: JG
authors.lastname: Verstuyft
authors.forename: C J
authors.initials: CJ
authors.lastname: Epstein
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D008076:Cholesterol, HDL; D004041:Dietary Fats; D008074:Lipoproteins; D002784:Cholesterol; D013482:Superoxide Dismutase