on March 16, 2006
Published online before print March 16, 2006, doi: 10.1161/01.ATV.0000217909.09198.d6
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Submitted on January 8, 2006
Accepted on March 3, 2006
12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E-Deficient Mice Through Activation of RhoA and NF-
B
David T. Bolick ;
From Cardiovascular Research Center, University of Virginia, Charlottesville.
* To whom correspondence should be addressed. E-mail: cch6n{at}virginia.edu.
Objectives--12/15 lipoxygenase (12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte:endothelial interactions in vivo in apolipoprotein E-deficient mice (apoEKO), a well-characterized mouse model of atherosclerosis.
Methods and Results--In apoEKO mice that are also deficient in 12/15LO (doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC (Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-
B. DoubleKO aorta displayed little nuclear localization of NF-B. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKC
significantly reduced NF-B activation, ICAM-1 induction, and monocyte adhesion to aorta.
Conclusions--We conclude that 12/15LO products activate endothelial rhoA and PKC. Activation of rhoA and PKC cause activation and translocation of NF-B to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice.
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