Rabbit models to study atherosclerosis and its complications - Transgenic vascular protein expression in vivo

Animal models of atherosclerosis often present limitations of transferability, since important hallmarks of human disease are not completely reproduced in other species. Rabbits have been used in several approaches: 1) inbred strains: Watanabe hereditary hyperlipidemic animals which express a defect in the LDL receptor, 2) transgenic rabbits, which overexpress human lipoproteins, and first knock-out rabbits. 3) native New Zealand white rabbits (NZW) fed with cholesterol-rich diet for at least 8 weeks represent the quickest way to establish arteriosclerosis. Rabbits are arguably the most sensitive animal species to cholesterol overload. Interventions in native or arteriosclerotic arteries are used to induce local thrombus formation, e.g. endothelial denudation or photochemical injury. In contrast to smaller animals, catheterisation of coronary arteries is feasible, whose external ligation serves to induce myocardial infarction. As biological endpoints, arterial vasoreactivity/endothelial dysfunction can be studied in analogy to measurements of brachial artery vasomotion in humans in response to increasing doses of acetylcholine or volume challenges. Tissue fixation allows studying vascular morphology, plaque sizes and thrombi after local interventions. Macrophage and T lymphocyte invasion can be investigated histologically. Positron emission tomography (PET/MRI) offers to measure plaques and content in vivo serially in the same animals. Local virally mediated gene transfer to atherosclerotic rabbit arteries has been established as a rapid and reproducible method to test interesting transgenes. Histological plaque features correspond well to alterations in patients (inflammation and lipid load). Thus, effects of any proteins can be studied directly in the arteriosclerotic disease background - much quicker than after germline transgenesis and cross-breeding.