12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-κB

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Abstract
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 12SHET... 12/15-lipoxygenase (12/15-LO) promotes monocyte:endothelial interactions and atherosclerosis. We report that 12/15-LO activation in endothelium activates the small GTPase RhoA which then activates PKCα and NFκB. The activation of this pathway increases endothelial ICAM-1 expression in vivo. ICAM-1 is a primary regulator of monocyte adhesion to endothelium.

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