Role of amyloid precursor protein and uncoupling protein 2 in atherosclerosis

Unstable human atherosclerotic plaques are characterized by a thin fibrous cap that contains few smooth muscle cells and numerous foam cells of macrophage origin. Phagocytosis of platelets by macrophages is an alternative mechanism of foam cell formation. Platelets contain amyloid precursor protein (APP) in their alpha-granules and can enter an atherosclerotic plaque through the microvasculature (leaky microvessels). We demonstrated for the first time that APP or APP-derived fragments are the effector molecules that induce macrophage activation after platelet phagocytosis. Uptake of APP-deficient platelets by macrophages did not result in macrophage activation, whereas phagocytosis of wild type platelets clearly activated macrophages. Studies with cholesterol-fed mice deficient in APP and apolipoprotein E (apoE) demonstrated that APP promotes atherogenesis and aggravates endothelial dysfunction.; Rupture-prone atherosclerotic plaques show an elevated temperature, but a molecular explanation for this phenomenon is unknown. We investigated whether mitochondrial uncoupling protein 2 (UCP2) could be involved, because this protein is a macrophage homologue of thermogenin in brown fat tissue. Immunohistochemistry, western blotting and quantitative PCR were used to detect UCP2 expression in human and rabbit atherosclerotic plaques. Temperature was measured in plaques using thermography catheters and in cultured cells using precision thermometers. UCP2 was abundantly expressed in subendothelial macrophages of atherosclerotic plaques but not in deeper layers of the plaque or in smooth muscle cells. Ex vivo temperature measurements in atherosclerotic rabbit thoracic aorta demonstrated a correlation between local plaque temperature, total macrophage mass and UCP2 expression. In vitro, chemical uncoupling of macrophages with NaCN resulted in heat production. Also overexpression of UCP2 in cultured cells led to a similar increase in temperature.; Since unstable (macrophage-rich) plaques have a higher temperature than stable (macrophage-poor) atherosclerotic plaques, UCP2 expression in macrophages can be considered a biochemical link between plaque temperature and vulnerability. The generated heat might be used to detect rupture-prone atherosclerotic plaques via thermography. If vulnerable plaques in coronary arteries can be detected by the generation of thermal maps, it would be possible to identify patients at risk for an acute coronary syndrome. Once identified, these patients can be treated earlier, resulting in risk reduction of acute coronary events.