FATTY STREAK FORMATION IN FAT-FED MICE EXPRESSING HUMAN COPPER-ZINC SUPEROXIDE-DISMUTASE

Studies in vitro have shown that copper-zinc super-oxide dismutase (Cu Zn-SOD) inhibits a number of events putatively involved in atherogenes is, including cell-mediated oxidation of LDL. To investigate whether i ncreased activity of CuZn-SOD reduces atherogenesis in vivo, we examin ed diet-induced fatty streak formation in CuZn-SOD transgenic mice (n = 24) as compared with their nontransgenic littermates (n = 28). Trans genic animals were originally created by introduction of an EcoRI-BamH I human genomic DNA fragment containing the CuZn-SOD gene and its regu latory elements into B6SJL zygotes. For the current studies, the trans gene 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 10 weeks of age and extendi ng for 18 weeks. At the end of the diet period, aortic SOD activity wa s 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 dityro sine) were either similar or lower in aorta and heart from transgenics as compared with nontransgenics, suggesting that amplification of CuZ n-SOD activity above the normal complement had modest inhibitory effec ts on basal oxidative stress in these tissues. CuZn-SOD overexpression did not reduce the extent of lesion development as analyzed by quanti tative lipid staining of serial sections of the proximal aorta; mean l esion areas (+/- SE) were 997 +/- 478 and 943 +/- 221 mu(2) in transge nics and nontransgenics, respectively. Notably, the range of values fo r lesion area was 2.2-fold greater in transgenics (0-8403 versus 0-386 8 mu(2) in nontransgenics). Moreover, within this group, lesion area s howed 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 the possibility that high tissue SOD activ ity may potentiate atherogenesis in fat-fed atherosclerosis-susceptibl e mice.