Transgenic rabbits as models for atherosclerosis research

Several characteristics of the rabbit make it an excellent model for the study of lipoprotein metabolism and atherosclerosis. New Zealand White (NZW) rabbits have low plasma total cholesterol concentrations, high cho- lesteryl ester transfer protein activity, low hepatic lipase (HL) activity, and lack an analogue of human apolipopro- tein (apo) A-II, providing a unique system in which to assess the effects of human transgenes on plasma lipoproteins and atherosclerosis susceptibility. Additionally, rabbit models of human lipoprotein disorders, such as the Watanabe Herita- ble Hyperlipidemic (WHHL) and St. Thomas' Hospital strains, models of familial hypercholesterolemia and famil- ial combined hyperlipidemia, respectively, allow for the as- sessment of candidate genes for potential use in the treat- ment of dyslipoproteinemic patients. To date, transgenes for human apo(a), apoA-I, apoB, apoE 2 , apoE 3 , HL, and lec- ithin:cholesterol acyltransferase (LCAT), as well as for rab- bit apolipoprotein B mRNA-editing enzyme catalytic poly- peptide 1 (APOBEC-1), have been expressed in NZW rab- bits, whereas only those for human apoA-I and LCAT have been introduced into the WHHL background. All of these transgenes have been shown to have significant effects on plasma lipoprotein concentrations. In both NZW and WHHL rabbits, human apoA-I expression was associated with a significant reduction in the extent of aortic athero- sclerosis, which was similarly the case for LCAT in rabbits having at least one functional LDL receptor allele. Con- versely, expression of apoE 2 in NZW rabbits caused in- creased susceptibility to atherosclerosis. These studies pro- vide new insights into the mechanisms responsible for the development of atherosclerosis, emphasizing the strength of the rabbit model in cardiovascular disease research. — Brousseau, M. E., and J. M. Hoeg. Transgenic rabbits as models for atherosclerosis research. J. Lipid Res. 1999. 40: 365-375.