Eicosanoids in sickle cell disease: potential relevance of 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid to the pathophysiology of vaso-occlusion.
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.
Setty
B N
BN
Department of Pediatrics, Thomas Jefferson University Medical School, Philadelphia, Pennsylvania, USA.
Chen
D
D
O'Neal
P
P
Littrell
J B
JB
Grossman
M H
MH
Stuart
M J
MJ
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000097:blood / Q000502:physiology* / Q000652:urine; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D002417:Cattle; D002448:Cell Adhesion; D002648:Child; D002675:Child, Preschool; D004730:Endothelium, Vascular / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D019007:P-Selectin; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid