5-Hydroxyeicosatetraenoic acid is a key intermediate of the arachidonate-dependent protective signaling in monocytes/macrophages exposed to peroxynitrite.

Endogenous generation of arachidonic acid via selective activation of cytosolic phospholipase A(2) has been implicated in the mechanism of monocytes/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger was shown to prevent the otherwise rapid onset of a mitochondrial permeability-transition (MPT)-dependent necrosis by causing the mitochondrial translocation of protein kinase C alpha (PKC alpha) and the ensuing cytosolic accumulation of the Bcl-2-antagonist of cell death (Bad), an event promoting the anti-MPT function of Bcl-2 (or Bcl-X-L). Here, we show that the effects on PKCa are not mediated directly by arachidonate but rather, by downstream products of the enzyme 5-lipoxygenase (5-LO). Peroxynitrite elicited the nuclear membrane translocation of 5-LO and enhanced its enzymatic activity via a mechanism sensitive to low concentrations of inhibitors of 5-LO or the 5-LO-activating protein, as well as to genetic depletion of the latter enzyme. Inhibition of 5-LO activity was invariably associated with the cytosolic localization of PKC alpha, the mitochondrial accumulation of Bad, and a rapid MPT-dependent necrosis. All these events were prevented by nanomolar concentrations of the 5-LO product 5-hydroxyeicosatetraenoic acid.