|[Frontiers in Bioscience 2, d298-308, June 15, 1997]|
TRANSGENIC RABBIT MODELS FOR THE STUDY OF ATHEROSCLEROSIS
John M. Taylor and Jianglin Fan
Gladstone Institute of Cardiovascular Disease, the Department of Physiology, and the Cardiovascular Research Institute, University of California, San Francisco, CA
An 85-kb human genomic fragment that spanned the complete human apoB gene was used to generate transgenic rabbits (49). Prior analysis of the expression of this fragment in transgenic mice showed that it was expressed at high levels only in the liver and not in any other tissue (50). Examination of the transgenic human apoB from rabbit plasma by gel electrophoresis and reaction with a panel of monoclonal antibodies demonstrated the presence of only the apoB100 form, which was indistinguishable from normal human apoB100. This finding confirmed that the transgene was probably expressed only in the liver of the rabbits, since the apoB100 mRNA would have been processed normally by the intestine to the B48 form. The concentrations of human apoB in three transgenic rabbit founders were 5, 40, and 100 mg/dl, but only the high expresser was characterized.
The apoB transgenic rabbits had threefold elevations in plasma cholesterol and triglycerides, compared to nontransgenic controls. In the transgenic rabbits, ~75% of the triglycerides and ~90% of the cholesterol were found in LDL. Compared to control LDL, the triglyceride-enriched transgenic LDL were smaller and more dense, and they were enriched in apoE and apoC-III. In transgenic rabbits, the HDL cholesterol also was significantly reduced, consistent with a reduction in the content of apoA-I in the HDL fractions. This lipoprotein profile suggests that the overexpression of apoB100 may have resulted in the direct production of LDL-sized particles, although this possibility remains to be tested. The lack of apoB -mRNA editing in the rabbit liver makes these animals particularly attractive for the study of LDL metabolism.