The long term objective of this proposal is to understand the role of marine lipids on lesion formation in atherosclerosis. The proposal is based on four observations: (1) that smooth muscle cell (SMC) proliferation is an early and critical event in the formation of occlusive atherosclerotic lesions; (2) that ingestion of fish or fish oils containing n-3 polyunsaturated fatty acids (PUFAs) inhibits intimal thickening in experimental animals, and may decrease the incidence of coronary heart disease in man; (3) that cultured endothelial cells (EC) produce mitogens, especially a platelet-derived growth factor-like protein, that stimulate SMC proliferation in vitro; and (4) that growth factor production by cultured EC is regulatable and, as we have recently observed, is inhibited by fish oil emulsions and certain modified lipoproteins. To explain these observations, we propose that ingestion of fish oils results in an elevated level of specific marine lipids in plasma lipoproteins, that the altered lipoproteins inhibit EC production of growth factors, and that this regulatory mechanism is in part responsible for the observed decrease in SMC growth, and the proposed benefits of this diet. This hypothesis will be tested by pursuit of the following specific aims: 1. To characterize and identify the lipid(s) in marine oils that specifically inhibits EC production of growth factors. 2. To determine if cellular processing is required for the expression of the inhibitory activity of marine lipids. 3. To determine the biosynthetic step(s) regulated by marine lipids that causes the inhibition of growth factor production by EC. 4. To determine whether physiological lipoproteins enriched with marine lipids inhibit EC production of growth factors. 5. To determine if marine lipids inhibit the proliferation of cultured vascular SMC. Answers to these questions of vascular cell biology should contribute to our understanding of the cellular interactions of EC and SMC. The mechanistic insights resulting from this work may help to explain the recent epidemiological studies which suggest that diets rich in n-3 PUFAs are associated with reduced incidence of coronary heart disease, and may eventually lead to the development of pharmacologic inhibitors of atherogenesis.
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