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).
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