Inducible nitric oxide synthase mediates cyclooxygenase nitration and eicosanoid production

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Nitric oxide (NO) modulates the activity of cyclooxygenase (COX) isoforms, thereby varying the biological levels of important cell signaling arachidonate-derived eicosanoids. The complex chemistry of NO and NO-derived species results in interactions with COX that either activates or suppresses its activity. We show that inducible NO synthase (iNOS) and COX-1 co-localize in atherosclerotic lesions from ApoE-null mouse aortae. Tyr nitration in COX-1 occurred in aortic lesions, but was markedly reduced in adjacent non-involved tissue. The absence of 3-NT in lesions from iNOS/ApoE double-null mice confirmed that NO derived from iNOS is essential for 3-NT modification of COX-1. Mass spectrometric studies specifically identified Tyr385 in the active site as a 3-NT modification site in purified COX-1, following peroxynitrite exposure. Our findings indicate that COX-mediated prostaglandin E2 synthesis is increased in cultured iNOS-null versus iNOS-expressing mouse aortic smooth muscle cells. These results indicate that NO derived from iNOS markedly suppresses COX activity in vascular cells. The extent to which iNOS-dependent nitration of Tyr in COX-1 contributes to perturbed eicosanoid biosynthesis in human atherosclerotic lesions awaits future investigations. This research was supported by the NIH, Pfizer Inc., Philip Morris USA Inc. and Philip Morris International.