Biological role of hepoxilins: Upregulation of phospholipid hydroperoxide glutathione peroxidase as a cellular response to oxidative stress?

Abstract

The 12S-lipoxygenase (12S-LOX) pathway of arachidonic acid (AA) metabolism is bifurcated at 12(S)-hydroperoxy-5Z,8Z,10E (12S-HpETE) in the reduction route to form 12S-hydroxy-eicosatetraenoic acid (12S-HETE) and in 8(S/R)-hydroxy-11(S),12S- trans-epoxyeicosa-5Z,9E,14Z-trienoic acid (HXA 3) synthase pathway, previously known as isomerization route, to form hepoxilins. Earlier we showed that the HXA 3 formation is restricted to cellular systems devoid of hydroperoxide reducing enzymes, e.g. GPxs, thus causing a persistent oxidative stress situation. Here, we show that HXA 3 at as low as 100 nM concentration upregulates phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA and protein expressions, whereas other metabolites of AA metabolism 12S-HpETE and 12S-HETE failed to stimulate the PHGPx. Moreover, the decrease in 12S-HpETE below a threshold value of the hydroperoxide tone causes both suppression of the overall 12S-LOX activity and a shift from HXA 3 formation towards 12S-HETE formation. We therefore propose that under persistent oxidative stress the formation of HXA 3 and the HXA 3-induced upregulation of PHGPx constitute a compensatory defense response to protect the vitality and functionality of the cell.