The goal of this work is to clarify the initiation and development of the lipid rich, necrotic core region of the atherosclerotic fibrous plaque. The core region plays a critical role in arterial ischemic disease, by weakening the arterial wall to allow rupture or sloughing of the intimal surface, leading to acute thrombosis? and ischemic sequelae such as myocardial infarction. Current studies focus on core region lipid deposition, as discerned in human autopsied and surgical arterial specimens and selected animal and in vitro model systems. Strong evidence has emerged' from these studies for several new concepts, including the following: First, core formation is a very early event in the formation of some, and perhaps most, fibrous plaques. Second, cholesterol crystallization initially occurs in a setting of pre-existent, intense extracellular lipid deposition. Third, although core formation deep in the intima is associated with the presence of foam cells in the superficial intima, early core lipid deposits do not result from foam cell necrosis. We hypothesize that a major portion of extracellular lipid deposits are assembled outside of cells from smaller lipid-rich particles, perhaps from bound lipoproteins or perhaps from individual lipid molecules transferred from freely diffusing lipoproteins. Planned studies are designed to demonstrate and this type of lipid deposition and elucidate its mechanism(s).
Specific aims are: (1) To determine whether a progressive transformation of-physical forms?and chemistry of lipid deposits may be seen in lesions of differing apparent age, (2) to determine whether continuing metabolism of extracellular lipid deposits occurs, particularly cholesteryl ester hydrolysis, (3) to determine the concentration, character, and ultrastructural localization of apolipoprotein antigens in lesioned and normal arterial intima, and (4) to determine when the interaction between lipoproteins and arterial fibrous proteins and proteoglycans can lead to sequestration of the lipoproteins.
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