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

摘要

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 100nM 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. Wetherefore 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.