XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Animal model will contribute to understand the link between atherosclerosis development and different pathological conditions.

Stockholm, Sweden -- Most of the session "Animal models in atherosclerosis" focused on transgenic models, except for the first presentation, by Dr. Julie Campbell (University of Queensland, Australia). Dr. Campbell presented her results on a rabbit model of restenosis obtained by double balloon injury. Rabbits are widely used animal models for atherosclerosis studies, since the anatomical/histological features of rabbit arterial plaques (induced by different approaches, from balloon injury to air desiccation, plus hypercholesterolemic diet) closely resemble those of humans. A second balloon injury at the site of the atherosclerotic plaque allows studies on the development of restenosis. This process was analyzed both in vivo by intravascular ultrasound (IVUS), and ex vivo, by histology. The results obtained underline similarities to the clinical features of restenosis; in fact, similar to what may be observed in humans, the luminal restenosis in this model is not only a consequence of intimal hyperplasia, but it is mostly due to a remodeling of the vessel.

All the following speakers gave new highlights on lipoprotein metabolism and the impact on atherosclerosis of human proteins involved in this pathway. The HDL system was the focus of Dr. Bryan Brewer's presentation; Dr. Brewer (NIH, Bethesda, MD, USA), first, gave an overview of his results on LCAT expression in different animal models, showing that an increased activity of this enzyme (responsible for cholesterol esterification in HDL particles) makes the reverse cholesterol transport pathway more efficient. This leads to the conclusion that LCAT could be a good target for antiatherosclerotic drugs. Subsequently, Dr. Brewer showed the results of his research on receptors for HDL catabolism. In vitro and in vivo studies on different animal models (such as the ob/ob mice or cubilin deficient dogs) showed evidence of two receptors responsible for HDL catabolism: one is the multifunctional receptor, LDL-receptor related protein (LRP) which would be involved in HDL uptake and degradation in the liver; the second, called megalin, would carry on the same function in the kidney. Interestingly, the two receptor genes display high sequence identity.

Dr. David Grass (DNX Transgenic Sciences, New Jersey, USA) presented two different transgenic mouse lines highly susceptible for atherosclerosis development. Expression of both human CETP (mice do not express CETP) and apolipoprotein B in the same transgenic mouse line causes dramatic changes in the lipoprotein profile, which becomes very similar to that of humans (ratio between LDL and HDL particles of 2:1 versus 1:4 of control mice). As expected, these mice have increased susceptibility to atherosclerosis. Another transgenic line, expressing Group II Phospholipase A2 (PLA2), whose levels are elevated in chronic inflammation, is characterized by a reduction in HDL plasma concentration, due to an accelerated catabolism of these particles. Moreover, HDL of PLA2 transgenic mice do not protect LDL from oxidation, as opposed to control mice. Interestingly, PLA2 mice develop atherosclerotic lesions even without any dietary stimulus; this model will contribute to understand the link between atherosclerosis development and inflammatory status.

Finally, apolipoprotein E and LDL receptor were the focus of the last two presentations. Dr. Maeda (University of North Carolina, USA) "humanized the lipid metabolism of mice" by the gene knock-in technique to study the interaction of the three human apoE isoforms with the human or murine LDL receptor. Dr. van Eck (LACDR Biopharmaceutics, The Netherlands), through transplants, in irradiated mice, of bone marrow obtained from different knock-out mouse lines, was able to demonstrate that macrophage apoE production and LDL receptor expression have opposite independent effects on atherosclerotic lesion development: apoE appears to be protective, whereas LDL receptor would induce accumulation of ß-VLDL into the macrophages and promote their transformation into foam cells.