|[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
Human apoA-I transgenic rabbits were generated with an 11-kb genomic fragment that directed expression specifically to the liver (53, 54). Several independent lines were established having plasma apoA-I levels ranging up to 175 mg/dl. The production of the corresponding endogenous rabbit apoA-I was depressed by the expression of human apoA-I, which became the major protein component of the transgenic rabbit HDL. The high-expresser apoA-I transgenic rabbits had elevated levels of HDL cholesterol with concomitant higher rates of cholesterol efflux compared to nontransgenic controls. There also was a substantial amount of pre-beta-migrating apoA-I-containing lipoproteins with HDL properties in the high-expresser transgenic rabbit. These particles may have formed as a result of a relative deficiency in apoA-II, which is normally a major component of several subclasses of HDL, or they might play a role as HDL precursors.
The diet of the apoA-I transgenic rabbits was supplemented with 0.3-0.5% cholesterol for 14 weeks, which raised plasma cholesterol levels to 1,200 mg/dl (55). Compared to cholesterol-matched nontransgenic controls, the transgenic rabbits had a significant 50% decrease in atherosclerotic lesion areas in their aortas. These findings are in accordance with a protective role for apoA-I-rich HDL in atherosclerosis.
Hoeg et al. have generated three founders that express human apoA-I using zygotes derived from WHHL donors (56). In transgenic rabbits that express 2 mg/dl of human apoA-I, there was an increase in HDL cholesterol from 16 to 32 mg/dl. This effect is quite interesting considering that a relatively low level of transgenic apoA-I is being expressed in these animals. This model may be especially useful for assessing the effect of increased HDL levels on the development of atherosclerosis.