HDL deficiency in genetically engineered mice requires elevated LDL to accelerate atherogenesis

Abstract

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 frequently although not invariably associated with atherosclerosis. To investigate atherosclerosis susceptibility associated with HDL 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 generally engineer mice, including mice with low HDL levels 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 levels due o the presence of the human apo B transgene and apo A-I knockout alleles, respectively (AI KO/Btg mice). After exposure to an atherogenic 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, 260±4630 μm2 for AI KO/Btg (n=2) versus 38, 120±3350 μm2 for Btg mice (n=19) (P