Published online before print September 15, 2005, doi: 10.1161/01.ATV.0000186181.19909.a6
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© 2005 American Heart Association, Inc.
Vascular Biology |
12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-
B
From the Cardiovascular Research Center (D.T.B., A.W., S.S., M.E.H., M.A.S., C.C.H.), and the Departments of Pharmacology (C.C.H.) and Microbiology (A.W.O., M.A.S.), University of Virginia, Charlottesville.
Correspondence to Catherine C. Hedrick, Cardiovascular Research Center, University of Virginia, PO Box 801394, 415 Lane Rd; MR5 Rm G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu
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-
B (NF-B) 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-B activation, ICAM-1 induction, and monocyte adhesion. Furthermore, we show that 12SHETE activates protein kinase C
, which forms a complex with active RhoA and is required for NF-B–dependent ICAM expression in response to 12SHETE.
Conclusions— The 12/15-LO pathway stimulates ICAM-1 expression through the RhoA/protein kinase C-dependent activation of NF-B. These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis.
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 PKC and NFB. The activation of this pathway increases endothelial ICAM-1 expression in vivo. ICAM-1 is a primary regulator of monocyte adhesion to endothelium.
Key Words: endothelium • 12/15-lipoxygenase • RhoA • ICAM-1
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