The monohydroxyeicosanoid 12(S)-hydroxy-5,8,10,14-eicosatetraenoic
acid (12-HETE), which is derived from oxygenation of
arachidonic acid by
12-lipoxygenase, is one of the major metabolites in platelets. In a recent study, we have showed that this
eicosanoid stimulated basal sickle-red-cell-endothelial-cell adhesion. To understand the pathophysiologic significance of
12-HETE, we measured the levels of this
eicosanoid in plasma and urine from children with
sickle cell disease. We found that as compared with controls, plasma
12-HETE levels are increased in patients with
sickle-cell disease in the steady state, and are increased further during vaso-occlusive crises. Urinary
12-HETE levels were also increased during the steady state. We also assessed plasma levels of soluble
P-selectin (another potential marker for platelet activation), and found changes in the levels of this marker similar to those seen with plasma
12-HETE. In additional studies, we found that
12-HETE enhanced
hypoxia-induced sickle-red-cell-endothelial adherence, and that this effect was mediated by potentiation of agonist-induced upregulation of the expression of the
mRNA for
vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells. Because
12-HETE appears to enhance both basal and agonist-induced sickle-red-cell adhesion, this metabolite could potentially play a role in the pathogenesis of the vaso-occlusive crisis (VOC) in
sickle-cell disease.