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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029680-09
Application #
3340782
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Guyton, J R; Klemp, K F (1996) Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol 16:4-11
Guyton, J R; Klemp, K F (1994) Development of the atherosclerotic core region. Chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb 14:1305-14
Guyton, J R; Klemp, K F (1993) Transitional features in human atherosclerosis. Intimal thickening, cholesterol clefts, and cell loss in human aortic fatty streaks. Am J Pathol 143:1444-57
Guyton, J R; Klemp, K F (1992) Early extracellular and cellular lipid deposits in aorta of cholesterol-fed rabbits. Am J Pathol 141:925-36
Guyton, J R; Klemp, K F; Mims, M P (1991) Altered ultrastructural morphology of self-aggregated low density lipoproteins: coalescence of lipid domains forming droplets and vesicles. J Lipid Res 32:953-62
Podet, E J; Shaffer, D R; Gianturco, S H et al. (1991) Interaction of low density lipoproteins with human aortic elastin. Arterioscler Thromb 11:116-22
Guyton, J R; Black, B L; Seidel, C L (1990) Focal toxicity of oxysterols in vascular smooth muscle cell culture. A model of the atherosclerotic core region. Am J Pathol 137:425-34
Guyton, J R; Shaffer, D R; Henry, P D (1989) Stress fibers in endothelial cells overlying atherosclerotic lesions in rabbit aorta. Am J Med Sci 298:79-82
Cushing, G L; Gaubatz, J W; Nava, M L et al. (1989) Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis 9:593-603
Guyton, J R; Klemp, K F (1989) The lipid-rich core region of human atherosclerotic fibrous plaques. Prevalence of small lipid droplets and vesicles by electron microscopy. Am J Pathol 134:705-17

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