[New insights into the etiopathogenesis of atherosclerosis and atherothrombosis].

The composition of an atherosclerotic plaque is an important determinant of plaque stability. Unstable rupture-prone plaques are characterized by a thin fibrous cap that contains few muscle cells. Several lines of evidence suggest that macrophage activation in the unstable shoulder of the plaque could contribute to plaque rupture by releasing toxic factors, possibly nitric oxide (NO), to smooth muscle cells. These macrophages are also involved in the uptake of apoptotic cells (AC) and the inefficient removal of the latter might contribute to the formation of the necrotic core through accumulation of necrotic debris. Furthermore, these AC rapidly expose phosphatidylserine on their surface, which is a potent substrate for the generation of thrombin and activation of the coagulation cascade. The following new insights in the etiopathogenesis of atherothrombosis will be discussed: (1) Human atherosclerotic plaques contain amyloid precursor protein (APP) and beta-amyloid peptide, which is cleaved from APP and which has been extensively studied in Alzheimer's disease. Macrophages phagocytose platelets,which contain APP in their alpha-granules and this platelet derived APP is subsequently proteolytically processed in these macrophages into beta-amyloid The latter is involved in the upregulation of the inducible NO-synthase which results in an increased production of toxic amounts of NO. (2) Phagocytosis of the pro-coagulant ACS is severely impaired in advanced human atherosclerotic plaques. Several factors present in the atherosclerotic lesion,such as accumulation of indigestible material in the macrophage cytoplasm,oxidative stress,and the presence of oxidized LDL or oxidized erythrocytes may contribute to the impairment of phagocytosis. (3) In order to study the impact of the impaired phagocytosis by the macrophages on the atherosclerotic lesion development,a double knock-out mouse was created which spontaneously develops atherosclerosis combined with a deficient phagocytotic capacity. Completely unexpected the double-knock out mouse developed an until now not described phenotype resembling the metabolic syndrome including a spectacular increase in body weight,accumulation of abdominal fat and fat in the liver and increased plasma levels of cholesterol. Furthermore the atherosclerotic lesions demonstrated a striking different morphology as compared to the lesions present in mice which spontaneously develop atherosclerosis.