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Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells.

American Journal of Physiology - Cell Physiology

Vascular Cell Adhesion Molecule-1, metabolism, Aspirin, pharmacology, Cyclooxygenase Inhibitors, Dose-Response Relationship, Drug, Drug Interactions, E-Selectin, Endothelium, Vascular, cytology, drug effects, enzymology, Gene Expression Regulation, Enzymologic, immunology, Heme Oxygenase (Decyclizing), genetics, Heme Oxygenase-1, Humans, Lipoxins, Membrane Proteins, Oligopeptides, Pertussis Toxin, RNA, Messenger, analysis, Signal Transduction, physiology, Umbilical Veins, Acute-Phase Reaction, drug therapy

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      Lipoxins (LX) and aspirin-triggered LX (ATL) are eicosanoids generated during inflammation via transcellular biosynthetic routes that elicit distinct anti-inflammatory and proresolution bioactions, including inhibition of leukocyte-mediated injury, stimulation of macrophage clearance of apoptotic neutrophils, repression of proinflammatory cytokine production, and inhibition of cell proliferation and migration. Recently, it was reported that aspirin induces heme oxygenase-1 (HO-1) expression on endothelial cells (EC) in a COX-independent manner, what confers protection against prooxidant insults. However, the underlying mechanisms remain unclear. In this study, we investigated whether an aspirin-triggered lipoxin A(4) stable analog, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A(4) (ATL-1) was able to induce endothelial HO-1. Western blot analysis showed that ATL-1 increased HO-1 protein expression associated with increased mRNA levels on EC in a time- and concentration-dependent fashion. This phenomenon appears to be mediated by the activation of the G protein-coupled LXA(4) receptor because pertussis toxin and Boc-2, a receptor antagonist, significantly inhibited ATL-1-induced HO-1 expression. We demonstrate that treatment of EC with ATL-1 inhibited VCAM and E-selectin expression induced by TNF-alpha or IL-1beta. This inhibitory effect of the analog is modulated by HO-1 because it was blocked by SnPPIX, a competitive inhibitor that blocks HO-1 activity. Our results establish that ATL-1 induces HO-1 in human EC, revealing an undescribed mechanism for the anti-inflammatory activity of these lipid mediators.

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