Dual regulation of glutathione peroxidase by docosahexaenoic acid in endothelial cells depending on concentration and vascular bed origin

Docosahexaenoic acid (DHA) has been reported to elicit oxidative stress, which in turn can induce antioxidant enzymes. Glutathione peroxidase (GPx) has received particular attention in this respect, as this enzyme is specifically required for the degradation of lipid hydroperoxides. Because we previously found that DHA could protect against oxidative stress when used in low amounts, we have compared the effect of a low (10 μM) versus high (100 μM) concentration of DHA on oxidant/antioxidant balance in bovine retinal and bovine aortic endothelial cells (BREC and BAEC). At 100 μM, DHA elicited a marked oxidative stress, as evidenced by high malondialdehyde levels and decreased plasmalogen phosphatidylethanolamine in both cells, and for BAEC only, a decrease of α-tocopherol. At 10 μM, DHA induced a slight increase of malondialdehyde in both cells, but did not affect α-tocopherol levels, which is indicative of a mild oxidative stress. In BREC, 10 μM DHA slightly but significantly decreased cytosolic GPx (cGPx) activity whereas 100 μM had no effect. In contrast, in BAEC, DHA 10 μM did not affect cGPx activity, whereas 100 μM increased it. The decreased cGPx activity in BREC was associated with a lower level of protein, suggesting a transcriptional and/or posttranscriptional effect. Phospholipid hydroperoxide GPx (PHGPx) activity was not modified by DHA at either concentration in BREC, whereas it was increased in BAEC when using 100 μM. Our results confirm that large amounts of DHA lead to oxidative stress, but do no support an antioxidant action of DHA at low concentration, in endothelium. Nevertheless, we showed that DHA can exert opposite effects on GPx regulation in endothelial cells, with regard to its concentration and to vascular bed origin.