HDL DEFICIENCY IN GENETICALLY-ENGINEERED MICE REQUIRES ELEVATED LDL TO ACCELERATE ATHEROGENESIS

In humans, a low HDL concentration is one of the strongest indicators of increased risk for coronary heart disease. Apolipoprotein A-I (apo A-I) synthetic defects result in extremely low HDL levels and are freq uently although not invariably associated with premature atheroscleros is. To inves- tigate atherosclerosis susceptibility associated with HD L deficiency alone and in combination with other risk factors, such as high levels of LDL, we have quantified diet-induced atherogenesis in a series of genetically engineered mice, including mice with low HDL l evels due to targeted disruption of both apo A-I alleles (AI KO mice), mice with high LDL levels due to expression of a human apolipoprotein B transgene (Btg mice), and mice with combined high LDL and low HDL l evels due to the presence of the human apo B transgene and apo A-I kno ckout alleles, respectively (AI KO/Btg mice). After exposure to an ath erogenic diet, AI KO and control mice had negligible lesions. All mice expressing the apo B transgene developed extensive lesions, but AI KO /Btg mice developed significantly larger lesions than Btg mice: 56, 26 0+/-4630 mu m(2) for AI KO/Btg (n=27) versus 38, 120+/-3350 mu m(2) fo r Btg mice (n=19) (P<.02). Results of this study, consistent with seve ral human epidemiological studies, indicate that HDL deficiency in the mouse does not by itself lead to the development of atherosclerosis b ut does increase atherosclerosis susceptibility when accompanied by ot her risk factors, in this case elevated LDL.