Plasma carotenoids are transported in lipoproteins and may protect them from oxidation, a process involved in atherosclerosis. When LDL was enriched with specific carotenoids only B-carotene was able to inhibit Cu-2+-mediated LDL oxidation, and its effect was modest. Thus, the protective effect of carotenoids on atherosclerosis may be unrelated to their presence as endogenous antioxidants in lipoproteins. Vascular cells can oxidize lipoproteins and carotenoids may alter their ability to do so. Metabolism of carotenoids may be necessary for their action. The proposed studies will define the mechanisms of cellular uptake and metabolism of carotenoids with particular focus on the interactions of lipoproteins and vascular endothelial cells since this may be important in atherogenesis.
In aim 1 the ability of specific carotenoids to inhibit the cell-mediated oxidation of lipoproteins will be assessed. Human endothelial cell hybridomas, EaHy cells, will be used to oxidize lipoproteins. The applicant will test the hypothesis that carotenoids, either in the lipoprotein per se or delivered to the cell, inhibit the cell-mediated oxidation of lipoproteins. The molecular mechanisms of this effect will be examined by testing the hypothesis that increasing the cellular content of carotenoids decreases the production of reactive oxygen species and increases the cell's resistance to oxidative damage.
In aim 2, the mechanisms of uptake of carotenoids will be determined in endothelial cells (EaHy-1), hepatoctyes (HepG2), and adipocytes (3T3-L1 cells). The applicant will test the hypothesis that cellular uptake of carotenoids is governed by the same cell-specific mechanisms involved in the uptake of other non-polar lipids.
In aim 3, the products of carotenoid metabolism will be defined in order to understand the mechanisms of carotenoid action. The applicant will test the hypothesis that endothelial cell-mediated oxidation of lipoprotein carotenoids leads to the formation of epoxide products, such as those known to be formed via oxidation reactions of carotenoids in chemical systems. In this aim the applicant will also ask if EaHy cells convert carotenoids to metabolic products. The applicant will test the hypothesis that the intracellular metabolism of lipoprotein-derived carotenoids proceeds via oxidation cleavage of the chain of double bonds.
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