Open Access12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-κB
Author(s) -
David T. Bolick,
A. Wayne Orr,
Angela Whetzel,
Suseela Srinivasan,
Melissa E. Hatley,
Martin A. Schwartz,
Catherine C. Hedrick
Publication year - 2005
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/01.atv.0000186181.19909.a6
Subject(s) - rhoa , microbiology and biotechnology , intercellular adhesion molecule 1 , proinflammatory cytokine , chemistry , monocyte , signal transduction , nf κb , nfkb1 , intercellular adhesion molecule , cell adhesion , biology , inflammation , cell adhesion molecule , biochemistry , immunology , transcription factor , cell , gene
Background— 12/15-lipoxygenase (12/15-LO) activity leads to the production of the proinflammatory eicosanoids 12-S -hydroxyeicosatetraenoic acid (12SHETE) and 13-S -hydroxyoctadecadienoic acid. We have previously shown a 3.5-fold increase in endothelial intercellular adhesion molecule (ICAM)-1 expression in mice overexpressing the 12/15-LO gene. We examined whether 12/15-LO activity regulated endothelial ICAM-1 expression.Methods and Results— Freshly isolated aortic endothelial cells (EC) from 12/15-LO transgenic mice had significantly greater nuclear factor-κB (NF-κB) activation and ICAM mRNA expression compared with C57BL/6J control. 12/15-LO transgenic EC showed elevated RhoA activity, and inhibition of RhoA using either C3 toxin or the Rho-kinase inhibitor Y-27632 blocked NF-κB activation, ICAM-1 induction, and monocyte adhesion. Furthermore, we show that 12SHETE activates protein kinase Cα, which forms a complex with active RhoA and is required for NF-κB–dependent ICAM expression in response to 12SHETE.Conclusions— The 12/15-LO pathway stimulates ICAM-1 expression through the RhoA/protein kinase Cα-dependent activation of NF-κB. These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis.