The continuing goal of this work is to clarify the initiation and development of the lipid-rich core region of the atherosclerotic fibrous plaque, as discerned primarily in human aorta and coronary arteries from autopsy cases. Studies performed in Years 01-02 have shown (1) consistent core development in small, distinct raised lesions, termed """"""""fibrolipid lesions"""""""" and regarded as fibrous plaque progenitors, (2) an absence of macrophage-like cells in the core, by routine electron microscopy, and early disappearance of elastin from the core, and (3) by ultrastructural lipid staining and quantitative localization, the predominance of elastin as a site for early lipid deposition in aortic intima. Based in part on these results, the following general hypothesis is proposed: Extracellular interactions between lipoproteins and connective tissue elements, especially elastin, play a central role in early core formation, although the metabolic activities of macrophages and smooth muscle cells modulate the process considerably.
The aims of the proposed studies are - (1) To determine the relationship of specifically determined constituents - including cholesterol, cholesteryl ester, and apoprotein B - to core region basophilia (light microscopy) and granular matrix (electron microscopy), (2) to determine the presence and location of certain cell types - macrophage, mature smooth muscle, secretory smooth muscle - identified immunologically and by other means, in and near the developing core region, (3) to confirm, by immunocytochemical and other methods, the extent of elastin participation in perifibrous lipid deposition and the impression of elastin disappearance from the core region, and (4) to determine the form in which lipoprotein lipid binds to elastin in vitro, the nature of the binding, and the reversibility and other characteristics of the process. Together these studies will contribute substantially toward proving and elucidating the stated hypothesis. The importance of the core region of the fibrous plaque is underscored by its role in causing plaque rupture or ulceration, leading to acute thrombotic or thromboembolic events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029680-06
Application #
3340780
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-01-01
Project End
1988-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
6
Fiscal Year
1988
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

Showing the most recent 10 out of 16 publications