Two of the major characteristics of atherogenesis in man are excessive cell births (proliferation) and excessive cell deaths (necrosis). One of these may be secondary to the other or they may instead (or in addition) have independent causes. A major goal of preventive or therapeutic measures should be to alter these phenomena (cell births and deaths) in a beneficial direction. The critical problems are to decide which direction is beneficial and to devise means to achieve the desired changes that will have the maximum probability of being acceptable to man. Most of the basic morphological and chemical features of human atherosclerotic lesions from early proliferative to late necrotic phases can be produced in appropriately chosen experimental animal models and even advanced lesions can be induced to regress by drastic diets (but the latter as known at present are unlikely to be acceptable to man). Also many features can be produced in in vitro systems. The overall objectives of the proposed projects are to utilize experimental animal models, aortic medial explant in vitro systems, and to a limited extent human autopsy material from G-6-PD mosaics to learn (1) principles regarding cell population dynamics (interplay of births and deaths) of arterial smooth muscle (SMC) and endothelial (EC) cells during all the phases of atherogenesis including regression and (2) principles regarding various dietary and drug regimens that can alter the involved processes in a beneficial direction and still be acceptable to man. The methods include 3H-thymidine autoradiography with detailed mathematical analyses, cholesterol enzymology and cholesterol balance in non-steady state situations, quantitative light and electron microscopy, arterial and whole carcass analyses for cholesterol, isotopic studies of synthesis of extracellular elements, tissue culture, and cell genetic probes (G-6-PD mosaicism). The experimental animals to be used for the most part are swine but some projects involve use of rabbits and hybrid hares with G-6-PD mosaicism. The dietary focus of the studies is on cholesterol (with its associated hyperlipidemia).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL020993-10
Application #
3097789
Study Section
(SRC)
Project Start
1977-08-01
Project End
1988-01-31
Budget Start
1986-08-01
Budget End
1988-01-31
Support Year
10
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Ho, H T; Kim, D N; Lee, K T (1989) Intestinal apolipoprotein B-48 synthesis and lymphatic cholesterol transport are lower in swine fed high fat, high cholesterol diet with soy protein than with casein. Atherosclerosis 77:15-23
Kim, D N; Ho, H T; Lawrence, D A et al. (1989) Modification of lipoprotein patterns and retardation of atherogenesis by a fish oil supplement to a hyperlipidemic diet for swine. Atherosclerosis 76:35-54
Murray, C D; Lee, K T; Kroms, M et al. (1988) Clonal nature of atherosclerotic plaques. Exp Mol Pathol 48:391-402
Kim, D N; Schmee, J; Ho, H T et al. (1988) The ""turning off"" of excessive cell replicative activity in advanced atherosclerotic lesions of swine by a regression diet. Atherosclerosis 71:131-42
Janakidevi, K; Murray, C D; Sell, C et al. (1988) Fluorometric analysis of DNA in cell cultures. Anal Biochem 172:78-81
Kim, D N; Scott, R F; Schmee, J et al. (1988) Endothelial cell denudation, labelling indices and monocyte attachment in advanced swine coronary artery lesions. Atherosclerosis 73:247-57
Lee, K T (1987) Experimental atherosclerosis in pigs. Yonsei Med J 28:1-5
Kim, D N; Schmee, J; Lee, K T et al. (1987) Atherosclerotic lesions in the coronary arteries of hyperlipidemic swine. Part 1. Cell increases, divisions, losses and cells of origin in first 90 days on diet. Atherosclerosis 64:231-42
Scott, R F; Kim, D N; Schmee, J et al. (1986) Atherosclerotic lesions in coronary arteries of hyperlipidemic swine. Part 2. Endothelial cell kinetics and leukocyte adherence associated with early lesions. Atherosclerosis 62:1-10
Scott, R F; Reidy, M A; Kim, D N et al. (1986) Intimal cell mass-derived atherosclerotic lesions in the abdominal aorta of hyperlipidemic swine. Part 2. Investigation of endothelial cell changes and leukocyte adherence associated with early smooth muscle cell proliferative activity. Atherosclerosis 62:27-38

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