Experiments performed in quadruplicate. Values are expressed as percentage of control for each enzyme ± S.D. Legend: GSP-px = glutathione peroxidase; GSH-S-ts = glutathione transferase; GSSG-red = glutathione reductase; SOD = superoxide dismutase; CAT = catalase. All figures reported are insignificantly different from controls.

reported that highly unsaturated n-3 fatty acids such as docosahexanoic acid (22:6 n-3) are inhibitors of endothelial activation, thus decreasing the expression of VCAM-1, E-selectin, ICAM-1, IL-6, and IL-8.43 Structure-activity analysis of the effects of unsaturated fatty acids on endothelial activation revealed that the inhibitory potency of an unsaturated fatty acid is roughly proportional to the number of double bonds accommodated in the carbon chain length. Thus, the n-3 polyunsaturated docosahexaenoic fatty acid that has six double bonds was found to be roughly six times more potent than oleate.64 Although oleic acid has only one double bond, the analysis of fatty acid incorporation in total cellular lipids pointed out that its addition to culture medium significantly increased the unsaturation index, an indicator of the number of double bonds present in the total cellular lipid pool.45 This happens because of a relatively selective replacement of saturated fatty acids by oleate, leaving higher unsaturated fatty acid pools relatively unaffected.46 These results led us to hypothesize a direct physical interference of oleate with generated ROS.64 This is in agreement with physio-chemical demonstrations of the possible reaction of superoxide anion even with the single double bond present in oleate65 involving the original formation of hydroperoxyl groups.

A current working hypothesis is therefore that oleate oxidation would scavenge superoxide anion. This perhaps increases the formation of hydroperoxides on the one hand, but also leads to a reduced probability for unmatched superoxide to be dismutated to hydrogen peroxide on the other. If hydrogen peroxide or some of its downstream products are directly responsible for NF-kB activation, then the interaction of oleate with superoxide anion, independent of any interference with enzyme activities controlling ROS levels, would be sufficient to explain the observed downstream effects of oleate as well as antioxidant olive oil polyphenols on endothelial activation (Figure 12.12).

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