Modulation of NF-κB activation by Peroxinitrite

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Peroxinitrite (ONOO^-, PN) is formed by the reaction of nitric oxide (NO) with superoxide (O₂·^-) [71], and is thus generated when the production of NO and O₂·^- is enhanced, notably under inflammatory conditions, circulatory shock and reperfusion injury [72].  PN formation also occurs in the heart during myocardial infraction [73] and heart failure [74].  PN is a highly oxidant and nitrating species causing important cellular injuries and is associated with numerous pathologies.  Recently, PN was also demonstrated to modify redox-sensitive cellular signalling pathways, such as the NF-κB pathway.  PN was shown by several authors to activate NF-κB in endothelial cells [75], leukocytes [76] and vascular smooth muscle cells [77].  However, a recent work carried out by Levrand et al. clearly demonstrated that PN is a potent inhibitor of NF-κB activation triggered by inflammatory stimuli in cardiac and endothelial cell lines [78].  They demonstrated that PN blocks IKKβ phosphorylation and activation, thereby preventing NF-κB nuclear translocation.  The PN inhibitory effect on NF-κB activation was further confirmed by Park et al. [79].  They showed that PN is capable of inducing p65 tyrosine nitration on Y66 and Y152, which in turn triggers replacement of p65/p50 dimers with the repressive p50/p50 complex on promoters and subsequent association of p65 with IκBα to promote export [79].  Therefore, the data collected about the effects of PN on the NF-κB pathway are apparently contradictory and still a matter of debate [80].