Biphasic modulation of atherosclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit.

There has been considerable debate about how copper status may affect the biochemical and cellular processes associated with atherogenesis. We have investigated the effects of graded dietary copper supplementation on processes likely to contribute to atherogenesis, using the cholesterol-fed New Zealand White rabbit model. Rabbits (n = 40) were fed a 0.25-1% cholesterol diet deficient in copper. Animals received either 0, 1, 3 or 20 mg copper/day and were killed after 13 weeks. Plasma cholesterol levels were similar in each dietary group. Aortic concentrations of copper were higher in the 20 mg copper/day animals compared to those receiving 0 mg copper/day (3.70 +/- 0.78 vs. 1.33 +/- 0.46 microg/g wet tissue; P < 0.05). Aortic superoxide dismutase activity was higher in animals receiving 20 mg copper/day (323 +/- 21 IU/mg tissue) compared to the other groups (187 +/- 21; 239 +/- 53; 201 +/- 33 IU/mg tissue) (P > 0.05). En face staining of aortae with oil red O showed that both high copper supplementation (20 mg/day) (67.1 +/- 5.5%) and a deficient diet (0 mg/day) (63.1 +/- 4.8%) was associated with significantly larger lesions (P < 0.05) compared to moderately supplemented animals (1 mg/day and 3 mg/day) (51.3 +/- 6.3 and 42.8 +/- 7.9%). These data indicate that in the cholesterol-fed rabbit, there is an optimal dietary copper intake and that dietary copper deficiency or excess are associated with an increased susceptibility to aortic atherosclerosis. Many Western diets contain insufficient copper and these findings indicate that a moderate dietary copper content may confer a degree of cardiac protection to the human population.