The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKCε inhibition

Abstract

A high intake of the omega-3 fatty acid docosahexaenoate [docosahexaenoic acid (DHA)] has been associated with systemic antiinflammatory effects and cardiovascular protection. Cyclooxygenase (COX)-2 is responsible for the overproduction of prostaglandins (PG) at inflammatory sites, and its expression is increased in atheroma. We studied the effects of DHA on COX-2 expression and activity in human saphenous vein endothelial cells challenged with proinflammatory stimuli. A ≥24-h exposure to DHA reduced COX-2 expression and activity induced by IL-1, without affecting COX-1 expression. DHA effect depended on the NF-κB-binding site in the COX-2 promoter. EMSAs confirmed that DHA attenuated NF-κB activation. Because MAPK, PKC, and NAD(P)H oxidase all participate in IL-1-mediated COX-2 expression, we also tested whether these enzymes were involved in DHA effects. Western blots showed that DHA blocked nuclear p65 NF-κB subunit translocation by decreasing cytokine-stimulated reactive oxygen species and ERK1/2 activation by effects on both NAD(P)H oxidase and PKCε activities. Finally, to address the question whether DHA itself or DHA-derived products were responsible for these effects, we inhibited the most important enzymes involved in polyunsaturated fatty acid metabolism, showing that 15-lipoxygenase-1 products mediate part of DHA effects. These studies provide a mechanistic basis for antiinflammatory and possibly plaque-stabilizing effects of DHA

RXR agonists inhibit high glucose-induced upregulation of inflammation by suppressing activation of the NADPH oxidase-nuclear factor-κB pathway in human endothelial cells

“…Our finding is consistent with previous observations that the fatty acid DHA, acting as a RXR ligand, inhibits growth and induces apoptosis by inhibiting NF-κB activity and suppressing cytokine production in macrophages (Narayanan et al, 2005;Weldon et al, 2007). DHA was also shown to suppress ROS production in endothelial cells by inhibiting NADPH oxidase activity (Massaro et al, 2006). In line with this, we have shown that the natural RXR ligand 9-cis-RA inhibited activation of the NADPH oxidase-NF-κB pathway, which attenuated inflammatory damage to endothelial cells.…”

Effects of dietary flaxseed on atherosclerotic plaque regression

“…Both PPAR-and PPAR-␣ activation have been implicated in a number of anti-inflammatory and antiatherosclerotic responses (16,40). Moreover, incorporation of n-3 fatty acids into cell membranes quenches ROS production, subsequently decreasing redox sensitive transcription factors, such as NF-B, that regulate proinflammatory and proatherogenic genes (19,41,42). Alternatively, the decreased C16:1/18:1 content that we found (Table 1) may be interpreted to suggest that stearoyl CoA desaturase (SCD)-1 activity was inhibited by flaxseed.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…The method of omega-3 mediated chemoprevention is believed to be partially due to the competition with AA for enzyme substrate. In addition, recent studies were able to assign its therapeutic properties to a marked increase in production of 13S-HODE as well as inhibition of protein kinase C (PKC)-and NADPH-mediated activation of NF-κB and ROS production respectively [154]. Intriguingly, a number of publications can be found suggesting both increased and decreased production of free radicals and ROS to be the reason for modification of carcinogenic processes by omega-3 [ 155 ].…”