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

• Published in: American Journal of Physiology: Cell Physiology Vol. 58; no. 3; pp. C557 - C563
• Main Authors: NASCIMENTO-SILVA, V, ARRUDA, M. A, BARJA-FIDALGO, C, VILLELA, C. G, FIERRO, I. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Physiological Society 01.09.2005
• Subjects: Aspirin; Biological and medical sciences; Cell metabolism, cell oxidation; Cell physiology; Cells; Enzymes; Fundamental and applied biological sciences. Psychology; Inflammation; Lipids; Molecular and cellular biology; Oxygen; signaling transduction; Signal transduction; Endothelial cell; Heme; Lipids; Inflammation; resolution of inflammation
• ISSN: 0363-6143; 1522-1563

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 A4 stable analog, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 (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 LXA4 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-1{beta}. 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. [PUBLICATION ABSTRACT]