Abstract
Omega-3 fatty acid products containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce the risk of cardiovascular disease, in part, by stimulating the endothelial formation of nitric oxide (NO), a potent vasoprotective factor. This study determined the mechanism leading to endothelial NO synthase (eNOS) activation in response to the highly active EPA:DHA 6:1 product. Vascular reactivity was assessed using porcine coronary artery rings suspended in organ chambers, the level of oxidative stress in coronary artery sections using the redox-sensitive probe, dihydroethidine, and the phosphorylation level of target proteins in cultured coronary artery endothelial cells by Western blot analysis. EPA:DHA 6:1 caused pronounced endothelium-dependent relaxations in porcine coronary artery rings. Relaxations to EPA:DHA 6:1 were slightly but significantly reduced by an eNOS inhibitor, not affected by inhibition of endothelium-dependent hyperpolarization and abolished by both treatments. Relaxations to EPA:DHA 6:1 were reduced by inhibitors of oxidative stress (MnTMPyP, PEG-catalase), an inhibitor of either Src kinase (PP2) or PI3-kinase (wortmannin), and intracellular copper chelating agents (neocuproine, tetrathiomolybdate) and were insensitive to cyclooxygenase inhibition (indomethacin), chelating agents for iron (desferroxamine), zinc (histidine), extracellular copper (bathocuproine). EPA:DHA 6:1 induced phosphorylation of Src, Akt and eNOS at Ser 1177; these effects were inhibited by MnTMPyP and PEG-catalase. EPA:DHA 6:1 induced the endothelial formation of ROS in coronary artery sections, this effect was inhibited by MnTMPyP, PEG-catalase, and intracellular copper chelating agents. EPA:DHA 6:1 causes endothelium-dependent NO-mediated relaxations in coronary artery rings, and this effect involves an intracellular copper-dependent event triggering the redox-sensitive PI3-kinase/Akt pathway to activate eNOS by phosphorylation at Ser 1177.
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