Fibrinogen and atherosclerosis: a study in transgenic mice

Abstract

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 APOE3-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 acute-phase 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 APOE3-Leiden 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 APOE3-Leiden mice on a high cholesterol diet did not change with time. The atherosclerosis measured in the APOE3-Leiden mice on the high cholesterol diet ranged from no atherosclerosis to the presence of foam cells and the development of fatty streaks. The plasma fibrinogen concentration in APOE deficient mice after 15 weeks on a high cholesterol diet was the same as in wild-type mice. The atherosclerosis in the APOE deficient mice ranged from intermediate lesions to severe plaque formation whereas the wild-type mice showed no signs of atherosclerosis. These results indicate that the plasma fibrinogen concentration in APOE3-Leiden mice and in APOE deficient mice is not elevated secondarily to an early, intermediate, or advanced stage of atherosclerotic plaque formation