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CELLULAR AND MOLECULAR

20-Hydroxyeicosatetraenoic Acid Stimulates Nuclear Factor-B Activation and the Production of Inflammatory Cytokines in Human Endothelial Cells

Department of Pharmacology, New York Medical College, Valhalla, New York (T.I., J.C., H.S., M.D.V., M.L.-S.); and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas (V.L.M., J.R.F.)

Endothelial dysfunction is associated with endothelial cell activation, i.e., up-regulation of surface cell adhesion molecules and the release of proinflammatory cytokines. 20-Hydroxyeicosatetraenoic acid (HETE), a major vasoactive eicosanoid in the microcirculation, has been implicated in the regulation of endothelial cell function through its angiogenic and pro-oxidative properties. We examined the effects of 20-HETE on endothelial cell activation in vitro. Cells transduced with adenovirus containing either CYP4A1 or CYP4A2 produced higher levels of 20-HETE, and they demonstrated increased expression levels of the adhesion molecule intercellular adhesion molecule (ICAM) (4–7-fold) and the oxidative stress marker 3-nitrotyrosine (2–3-fold) compared with cells transduced with control adenovirus. Treatment of cells with 20-HETE markedly increased levels of prostaglandin (PG) E₂ and 8-epi-isoprostane PGF₂, commonly used markers of activation and oxidative stress, and most prominently, interleukin-8, a potent neutrophil chemotactic factor whose overproduction by the endothelium is a key feature of vascular injury. 20-HETE at nanomolar concentrations increased inhibitor of nuclear factor-B phosphorylation by 2 to 5-fold within 5 min, which was followed with increased nuclear translocation of nuclear factor-B (NF-B). Likewise, 20-HETE activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway by stimulating phosphorylation of ERK1/2. Inhibition of NF-B activation and inhibition of ERK1/2 phosphorylation inhibited 20-HETE-induced ICAM expression. It seems that 20-HETE triggers NF-B and MAPK/ERK activation and that both signaling pathways participate in the cellular mechanisms by which 20-HETE activates vascular endothelial cells.

Address correspondence to: Dr. Michal Laniado-Schwartzman, Department of Pharmacology, New York Medical College, 15 Dana Rd., Valhalla, NY 10595. E-mail: michal_schwartzman{at}nymc.edu

This article has been cited by other articles:

				A. Dhanasekaran, S. Bodiga, S. Gruenloh, Y. Gao, L. Dunn, J. R. Falck, J. N. Buonaccorsi, M. Medhora, and E. R. Jacobs 20-HETE increases survival and decreases apoptosis in pulmonary arteries and pulmonary artery endothelial cells Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H777 - H786. [Abstract] [Full Text] [PDF]