Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice

Estrogens and immunity against LDL could be important in atherogenesis. Herein, we describe the development of atherosclerotic lesions and cellular immune responses to modified LDL in male and female apoE knockout (E0) mice over time, and the effect of 17β-estradiol on atherosclerosis-related cellular immunity. Animals were studied after 16 or 48 weeks of normocholesterol diet. Aortic lesions, lymphocyte populations, and the cellular immune response against modified LDL, with or without 17β-estradiol, were analyzed. Atherosclerotic lesions were larger and more advanced in young female than in male E0 mice. In older mice, no significant difference in lesion size or maturity was discerned between males and females. In spleen cell cultures of young females, addition of 17β-estradiol induced a proliferative T-cell response to oxidized LDL, while no such effect was seen in males. In similar cultures from old E0 mice, T-cells from female animals were activated by oxidized LDL even in the absence of exogenous estrogens. These data show important sex differences in the development of atherosclerosis. They suggest that these differences may be related to sex differences in the cellular immune responses to the atherosclerosis-related autoantigen, oxidized LDL.