Fibrinogen and atherosclerosis: A study in transgenic mice

Atherosclerosis is a multifactorial disease that is influenced by both genetic and environmental factors. Recent epidemiological studies have shown that the combination of elevated VLDL/LDL concentrations and elevated fibrinogen levels results in a strong increase of the risk for cardiovascular disease as compared to the individual risk factors. In humans, controlled studies on the relative contribution of the different factors are hampered by the heterogeneity in both environmental and genetic factors. To circumvent these limitations the APOES-Leiden transgenic mice model was developed. This model provides the opportunity to induce, modulate and measure atherosclerosis in a quantitative and standardized manner. The causal relation between increased VLDL/LDL levels and atherosclerosis has been well established, whereas for fibrinogen such a causative relationship is still uncertain. Because fibrinogen is an acutephase protein, we studied the possibility that plasma fibrinogen is a marker of the disease and becomes elevated as a consequence of inflammatory reactions that occur during the development of atherosclerotic plaques. The APOESLeiden mice were put on high cholesterol diet and at time intervals ranging from 4 to 30 weeks the plasma fibrinogen concentration was measured by a clotting rate assay and an ELISA. The progression of atherosclerosis in these mice was analyzed by histochemical methods. The fibrinogen levels in the plasma of APOES-Leiden mice on a high cholesterol diet did not change with time and were similar to the levels in APOES-Leiden mice which were on a regular mouse diet. The atherosclerosis measured in the APOES-Leiden mice on the high cholesterol diet ranged from no atherosclerosis to the presence of foam cells and the development of fatty streaks. The APOES-Leiden mice on regular diet showed no signs of atherosclerosis after 30 weeks. These results indicate that the fibrinogen concentration in the APOES-Leiden mice is not elevated secondarily to an early stage of atherosclerotic plaque formation and that the clotting properties of the fibrinogen molecules remain unchanged. Whether more advanced stages of plaque formation induce an increase in plasma fibrinogen needs to be determined. Also the role of fibrinogen as a causal factor should be assessed. © Pearson Professional Ltd 1996.