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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1734-1740.)
© 1997 American Heart Association, Inc.

Articles

Fatty Streak Formation in Fat-Fed Mice Expressing Human Copper-Zinc Superoxide Dismutase

Diane L. Tribble; Elaine L. Gong; Christiaan Leeuwenburgh; Jay W. Heinecke; Elaine L. Carlson; Judy G. Verstuyft; ; Charles J. Epstein

From the Department of Molecular and Nuclear Medicine, Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley, Calif. (D.L.T., E.L.G., J.G.V.), the Department of Medicine, Washington University, St. Louis, Mo. (C.L., J.W.H.), and the Department of Pediatrics, University of California, San Francisco, Calif. (E.L.C., C.J.E.).

Correspondence to Dr. Diane L. Tribble, Donner Laboratory, Room 465, University of California, Berkeley, CA 94720.

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 10 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 µ² 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 µ² 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 CuZn-SOD over expression, and the possibility that high tissue SOD activity may potentiate atherogenesis in fat-fed atherosclerosis-susceptible mice.

Key Words: atherogenesis • diet • oxidation • transgenic mice

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