5-Lipoxygenase plays a pivotal role in endothelial adhesion of monocytes via an increased expression of Mac-1

Abstract

AIMS: 5-Lipoxygenase (5-LO) is known to participate in the pathogenesis of atherosclerosis; however, the underlying mechanisms are unclear. Thus, this study investigated the molecular mechanisms responsible for 5-LO expression in monocytes as well as the role of 5-LO in monocyte adhesion to the vascular endothelium, which is a key early event in macrophage foam cell formation. METHODS AND RESULTS: An en face immunohistochemistry of endothelial surfaces revealed a marked increase in monocyte adhesion to the aortic endothelium in wild-type (WT) mice treated with lipopolysaccharide (LPS), which was significantly attenuated in 5-LO((-/-)) mice. Likewise, the adhesion capacity of primary monocytes isolated from LPS-treated WT mice was higher than those of monocytes from 5-LO((-/-)) mice. In in vitro study, LPS increased monocyte adhesion to endothelial cells with an enhanced Mac-1 expression. These were attenuated by a 5-LO inhibitor, MK886, as well as by molecular depletion of 5-LO in monocytes. Furthermore, LPS-induced Mac-1 expression on monocytes was significantly inhibited by pre-treatment with U-75302, a BLT1-receptor antagonist, suggesting a pivotal role of 5-LO-derived leukotrienes. In promoter activity analysis and chromatin immunoprecipitation assays to identify transcription factors involved in 5-LO expression, both NF-κB and Sp1 played central roles to increase 5-LO expression in LPS-treated monocytes. CONCLUSION: 5-LO expression in monocytes is modulated via NF-κB and Sp1 signalling pathways, and 5-LO plays a pivotal role in LPS-mediated monocyte adhesion to the vascular endothelium through an increased expression of Mac-1 on monocytes.