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 results in extremely low HDL levels and are frequently although not invariably associated with premature 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 genetically engineered 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 to 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 micron 2 for AI KO/Btg (n = 27) versus 38, 120 +/- 3350 micron 2 for Btg mice (n = 19) (P < .02). Results of this study, consistent with several human epidemiological studies, indicate that HDL deficiency in the mouse does not by itself lead to the development of atherosclerosis but does increase atherosclerosis susceptibility when accompanied by other risk factors, in this case elevated LDL.
Hughes
S D
SD
Human Genome Center, Lawrence Berkeley Laboratory, Calif 94720, USA.
Verstuyft
J
J
Rubin
E M
EM
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics*; D005818:Genetic Engineering; D005838:Genotype; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000172:deficiency* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D013997:Time Factors
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL