Nitrated fatty acids (NFAs) are α,β-unsaturated keto derivatives of ω-3 fatty acids formed from redox reactions of nitric oxide and nitrite and have recently emerged as anti-inflammatory agents that act as electrophiles. NFAs activate Nrf2 and PPARγ signaling and inhibit NF-κB. Recent data suggest a role in inhibition of reactive oxygen species (ROS) production. This function however, remains largely unexplored. The Nox family of oxidases is a major source of ROS implicated in hypertension and other cardiovascular diseases (CVDs). Here we postulate that the NFA nitro-oleic acid (OA-NO
2
) specifically inhibits ROS production by the Nox1 and Nox2 oxidases. Treatment of canonical Nox1-expressing COS-7 cells with OA-NO
2
vs its oleic acid (OA) control resulted in a concentration-dependent inhibition of ROS production (101.5, 98.9, 91.7, 94.8, 54.2, and 45.5 % of vehicle treated groups for 0.1, 1, 2, 4, 8, and 10 μM OA-NO
2
, respectively), with an IC
50
of 6.5 μM. Treatment of phorbol ester (PMA)-stimulated Nox2-expressing COS-7 cells yielded similar results (103.6, 106.6, 112.2, 102.1, 51.8 and 35.1 % vehicle treated groups for the same OA-NO
2
concentration range) with an IC
50
of 7.0 μM. Treatment with the same OA-NO
2
concentrations of Nox4- or Nox5-expressing COS-7 cells did not result in any inhibition. The effects of OA-NO
2
on Nox1 and Nox2 were unique to its electrophilic unsaturated keto structure, as OA (lacking NO
2
group), palmitic acid (lacking both double bond and NO
2
group) and linoleic acid (containing two
cis
double bonds) did not result in any inhibition, demonstrating that fatty acids other than NFAs are incapable of this inhibition. Moreover, experiments using potassium superoxide (O
2
•-
) ruled out any scavenging effects of OA-NO
2
on O
2
•-
. Finally, 10 μM OA-NO
2
inhibited both angiotensin II (AngII)- and PMA-stimulated O
2
•-
in rat aortic smooth muscle cells (4.4 ± 0.9, 10.8 ± 1.7 and 9.0 ± 2.5 in OA-treated vehicle, AngII and PMA groups vs. 5.8 ± 0.6, 5.7 ± 0.3 and 3.3 ± 1.0 pmol O
2
•-
/min/mg protein in OA-NO
2
-treated vehicle, AngII and PMA groups, respectively). Taken together, these results identify NFAs as potent inhibitors of Nox1- and Nox2-derived ROS raising the possibility for their use as therapeutic agents to treat hypertension and other CVDs.
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