Type VIII collagen is a short-chain collagen that is present in increased amounts in atherosclerotic lesions. Although the physiological function of this matrix protein is unclear, recent data suggest an important role in tissue remodeling. Type VIII collagen in the atherosclerotic lesion is mainly derived from smooth muscle cells. We now show that macrophages in the atherosclerotic vessel wall and monocytes in adjacent mural thrombi also express type VIII collagen. We demonstrated this using a novel combined fluorescence technique that simultaneously stains, within the same tissue section, specific RNAs by in situ hybridization and proteins by indirect immunofluorescence. In culture, human monocyte/macrophages expressed type VIII collagen at all time points from 1 h to 3 wk after isolation. Western blotting and immunoprecipitation also revealed secretion of type VIII collagen into the medium of 14-day-old macrophages. Because this is the first report of secretion of a collagen by macrophages, we tested the effect of lipopolysaccharide (LPS) and interferon gamma, substances that stimulate macrophages to secrete lytic enzymes, on macrophage expression of type VIII collagen. LPS and interferon gamma decreased expression of type VIII collagen. By contrast, secretion of matrix metalloproteinase 1 (MMP 1) was increased, indicating a switch from a collagen-producing to a degradative phenotype. Double in situ hybridization studies of expression of type VIII collagen and MMP 1 in human coronary arteries showed that in regions important for plaque stability, the ratio of MMP 1 RNA to macrophage type VIII collagen RNA varies widely, indicating that the transition from one phenotype to the other that we observed in vitro may also occur in vivo.
T h e r e ' s m o r e t h a n o n e w a y t o s i n k a s h i p , a s D o n a l d S a n d e r s k n o w s . P r e s i d e n t o f t h e I n s t i t u t e f o r t h e V i s u a l i z a t i o n o f H i s t o r y i n W i l l i am s t o w n , M a s s a c h u
FRI and FMT using "smart" protease sensing probes permits detection of experimental spontaneous breast cancers. Because the expression levels of various proteases correlate with patient outcome, this technique may not only help to detect, but also to differentiate breast cancers noninvasively.
Abstract-By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet-and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability. Key Words: atherosclerosis Ⅲ plaque rupture Ⅲ pathophysiology Ⅲ animal models M ost of the middle-aged and elderly population in the developed world and in many parts of the developing world have atherosclerosis, and about a quarter will die of it. Much has been achieved by conventional measures to prevent the development of atherosclerosis, but the outcome of persons suffering a coronary occlusion has not changed that much over the years. Nearly half of all people who develop a first acute myocardial infarction will be dead within a month. For this reason we urgently need to understand what leads to the fatal event and to identify and test treatments that prevent it from occurring. Up to quite recently, it was assumed that the risk of death was directly related to the burden of disease: the greater the extent of atherosclerosis, the higher the risk. About 10 years ago, a paradigm shift occurred when it was realized that the fatal complications of atherosclerosis, myocardial infarction, and stroke do not necessarily occur in those with the heaviest burden of disease. Rather, acute blockage of an artery in the brain or heart is often caused by a clot that occurs at the site of rupture of a so-called "vulnerable plaque." Such vulnerable plaques consist of a lipid-rich thrombogenic core that is separated from the arterial bloodstream only by a slender and fragile layer of tissue, the The search for an animal model of atherosclerotic plaque rupture should be seen against this background. Also, it should be remembered that it has never been easy to find a good animal model of the atherosclerotic process per se. Atherosclerosis is a disease that really only affects humans and 1 or 2 other species, such as the pig and certain primates, with the result that researchers have had to resort to genetically modified models to even partially reproduce the condition.Several reviews dealing with plaque instability in animal models have been published within the last few years, 2-5 including 1 in this journal. 6 The Macrophage Function and Stability of the Atherosclerotic Plaque (MAFAPS) consortium was established as part of the Fifth Framework Program of the ...
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