Abstract
AimsOmega-3 fatty acid products containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have vasoprotective effects, in part, by stimulating the endothelial formation of nitric oxide (NO). This study determined the role of the EPA:DHA ratio and amount, and characterized the mechanism leading to endothelial NO synthase (eNOS) activation.Methods and ResultsEPA:DHA 6∶1 and 9∶1 caused significantly greater endothelium-dependent relaxations in porcine coronary artery rings than EPA:DHA 3∶1, 1∶1, 1∶3, 1∶6, 1∶9, EPA and DHA alone, and EPA:DHA 6∶1 with a reduced EPA + DHA amount, which were inhibited by an eNOS inhibitor. Relaxations to EPA:DHA 6∶1 were insensitive to cyclooxygenase inhibition, and reduced by inhibitors of either oxidative stress, Src kinase, PI3-kinase, p38 MAPK, MEK, or JNK. EPA:DHA 6∶1 induced phosphorylation of Src, Akt, p38 MAPK, ERK, JNK and eNOS; these effects were inhibited by MnTMPyP. EPA:DHA 6∶1 induced the endothelial formation of ROS in coronary artery sections as assessed by dihydroethidium, and of superoxide anions and hydrogen peroxide in cultured endothelial cells as assessed by electron spin resonance with the spin probe CMH, and the Amplex Red based assay, respectively.ConclusionOmega-3 fatty acids cause endothelium-dependent NO-mediated relaxations in coronary artery rings, which are dependent on the EPA:DHA ratio and amount, and involve an intracellular activation of the redox-sensitive PI3-kinase/Akt and MAPKs pathways to activate eNOS.
Highlights
Many prospective cohort studies and meta-analyses have provided evidence that fish consumption, especially oily fish, with high amounts of omega-3 fatty acids, including eicosapentaenoic acid (EPA, C20:5 v-3) and docosahexaenoic acid (DHA, C22:6 v-3), or supplementation with omega-3 fatty acids reduce cardiovascular mortality in patients with heart disease [1,2]
Omega-3 fatty acids cause endothelium-dependent nitric oxide (NO)-mediated relaxations in coronary artery rings, which are dependent on the EPA:DHA ratio and amount, and involve an intracellular activation of the redox-sensitive PI3-kinase/ Akt and MAPKs pathways to activate endothelial NO synthase (eNOS)
These findings indicate that omega-3 fatty acids are inducers of endotheliumdependent relaxations in coronary artery rings, and that this effect is dependent on the EPA:DHA ratio and on the EPA plus DHA amount
Summary
Many prospective cohort studies and meta-analyses have provided evidence that fish consumption, especially oily fish (e.g., salmon, trout, herring, sardines, and mackerel), with high amounts of omega-3 fatty acids, including eicosapentaenoic acid (EPA, C20:5 v-3) and docosahexaenoic acid (DHA, C22:6 v-3), or supplementation with omega-3 fatty acids reduce cardiovascular mortality in patients with heart disease [1,2]. More recent double-blind trials did not show an effect of an additional amount of EPA plus DHA on major cardiovascular endpoints in patients with coronary artery disease or after myocardial infarction [4,5]. Such differences have been explained by differences in study design, the fact that patients in the more recent trials were optimally treated by antithrombotics and by antihypertensives and statins, and possibly due to the use of different doses, sources (oily fish or fish-oil supplements), and formulation of EPA and/or DHA [6]. Thereafter, the endothelium-dependent relaxation to one of the most active omega-3 products was further characterized and in particular the role of endothelium-derived NO, EDH and vasoactive prostanoids, and the signal transduction pathway leading to eNOS activation were determined
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