This is part of an investigator initiated multicenter co-operative study aimed at studying the pathologic determinants of atherosclerosis in youth. In the last several years it has become apparent that several factors may be involved in the pathogenesis of atherosclerosis. Therefore it is our aim to study early lesions of atherosclerosis that may be seen in young adults and to compare these to the lesions seen in adult patients with coronary heart disease. This application proposes to investigate two biochemical parameters - collagen and biogenic amines - which may provide insights into the molecular basis of this disease. i) Current evidence indicates that the atherosclerotic plaque is composed predominantly of smooth muscle cells and the extracellular components which they synthesize, and these components are collagen. To date, however, a paucity of information exists in regard to the precise amounts of the major genetic types of collagen (Types I, III, IV and V) present in the normal artery in mature plaques or fatty streaks. The objectives of the first aspect of this proposal are to extract the collagens, using limited pepsin digestion, from both normal and diseased artery samples, to fractionate this mixture into preparations containing predominantly one genetic type of collagen, to quantitate the amount of collagen in each fraction, and to assess if the ratio of the genetic types of collagen are altered from the normal in the atherosclerotic lesions. Such information will not only firmly establish the collagen content of the normal artery but an observed change in this biochemical parameter associated with the atherogenic samples may provide insights into the pathogenesis of this disease process. ii) The role of biogenic amines in the formation and progression of atherosclerotic plaques. Coronary artery spasm has been suggested as a possible mechanism of endothelial injury which in the setting of the well established risk factors may induce atherosclerosis. It has recently been shown that the histamine contents of atherosclerotic coronary arteries is increased and that the coronary segments in vitro are hyper-reactive to histamine. Therefore, by studying early atherosclerotic plaques in young adults may indicate that histamine may be an important regulator of atherosclerosis. We will be measuring total histamine, serotonin, catecholamine content and will correlate the histamine content to the mast cell presence in the adventitia and its extent and also to the type and amount of atherosclerosis. These three factors may be intimately related. Thus far, no studies of biogenic amines have been carried out in early lesions of atherosclerosis. We also intend to contrast the atherosclerotic plaques present in coronary arteries of young adults with the type of lesions and reactivity of coronary segments of autopsy patients who die of coronary heart disease.
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