The overall objective of this study is to characterize the role of the acute-phase protein, C-reactive protein (CRP), in the pathogenesis of atherosclerosis. Previous studies have demonstrated the presence of CRP in human atherosclerotic lesions. Using immunohistochemical procedures, the localization of CRP in human atherosclerotic lesions will be determined and compared with the histochemical localization of other plasma proteins such as lipoproteins, complement, and albumin. These studies will correlate the localization of CRP with specific lesion characteristics such as the presence of smooth muscle cells, macrophage foam cells, necrosis, fibrosis, etc., as well as with perimortem plasma CRP concentrations. An attempt will be made to isolate CRP-lipoprotein complexes from human atherosclerotic lesions and to develop procedures for the formation of CRP-lipoprotein complexes in vitro. The metabolism of these complexes by macrophages, smooth muscle cells, and by organ cultures of arterial tissue will be studied to determine the cells responsible for uptake. If these studies suggest specific receptor-mediated mechanisms, then the nature of these receptors will be investigated by competition experiments using a variety of normal and abnormal lipoproteins, Fc fragments, etc. Purified CRP and lipoproteins will be obtained from humans, rabbits, and atherosclerosis-susceptible White Carneau pigeons. The effect of an induced acute-phase response on the development of atherosclerosis in rabbits and pigeons will be studied as well. As a result of these studies, it should be possible to determine if CRP, and its interactions with lipoproteins and cells, play a role in the development of atherosclerosis and to suggest potential pathogenic mechanisms by which this may occur.
