EFFECT OF THE ANTIOXIDANT N,N'-DIPHENYL 1,4-PHENYLENEDIAMINE (DPPD) ON ATHEROSCLEROSIS IN APOE-DEFICIENT MICE

Apolipoprotein (ape) E-deficient mice develop atherosclerotic lesions that contain epitopes formed during the oxidative modification of lipo proteins, and they demonstrate high titers of circulating autoantibodi es against such epitopes, suggesting that this murine strain may provi de a model to investigate the atherogenic mechanisms of oxidized lipop roteins (Palinski et al, Arterioscler Thromb. 1994;14:605-616). To tes t the hypothesis that lipoprotein oxidation contributes to lesion form ation in apoE-deficient mice, we studied the effect of the antioxidant N,N'-diphenyl 1,4-phenylenediamine (DPPD) in mice fed a high-fat diet containing 0.15% cholesterol. Animals were divided into two subgroups matched for sex and plasma cholesterol levels, and DPPD (0.5% wt/wt) was added to the diet of one subgroup. Throughout the 6 months of inte rvention, DPPD treatment had no significant effect on plasma cholester ol. Plasma levels of DPPD at the end of the experiment were 33.1 mu mo l/L. As judged by resistance to loss of polyunsaturated fatty acids, l ipoproteins (d <1.019 g/mL) from DPPD-treated animals showed greater r esistance to copper-induced oxidation than lipoproteins from control a nimals. In addition, there was a greater than twofold prolongation of the lag time in the formation of conjugated dienes in the LDL and IDL fractions of DPPD-treated mice. Atherosclerosis was significantly redu ced, by 36% in the DPPD-treated mice (14.0+/-4.53% of aortic surface a rea versus 21.9+/-11.6%; n=32; P<.02). These results are consistent wi th the hypothesis that lipoprotein oxidation contributes to atherogene sis in apoE-deficient mice. However, further studies with other antiox idants are needed to validate this hypothesis.