INHIBITION OF ATHEROSCLEROSIS DEVELOPMENT IN CHOLESTEROL-FED HUMAN APOLIPOPROTEIN A-I-TRANSGENIC RABBITS

Background Prospective epidemiological studies support the hypothesis that high levels of high-density lipoprotein (HDL) cholesterol and apo lipoprotein (ape) A-I limit atherosclerosis development. However; more data from studies with animal models of atherosclerosis that resemble the human disease are required to demonstrate the effect of apo A-I i n the inhibition of atherogenesis. The rabbit is a good animal model f or human atherosclerosis. Methods and Results Human apo A-I-transgenic rabbits have been produced, and we have evaluated the effect of apo A -I on the development of atherosclerosis in transgenic rabbits fed a c holesterol-rich diet for 14 weeks. Plasma cholesterol levels of athero genic apo B-containing lipoproteins were similar for transgenic and co ntrol rabbits (>1000 mg/dL), while plasma levels of HDL cholesterol in the transgenic group were always about twice that of the control grou p (68+/-11 versus 37+/-3 mg/dL at 14 weeks; P <.001). At the end of th e experiment, the amount of aortic surface area covered by lesions as well as the amount of lipid accumulation in the aorta were significant ly less in transgenic rabbits compared with the control group (15+/-12 % versus 30+/-8%, P <.0027 for the surface area of the thoracic aorta; 116+/-31 versus 247+/-39 mu mol/g aorta, P <.006 for cholesterol cont ent in total aorta). Conclusions Overexpression of human apo A-I in ra bbits inhibits the development of atherosclerosis in this animal model that resembles, in many respects, human atherosclerosis.