12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-kappaB.
OBJECTIVE
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.


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-kappaB. DoubleKO aorta displayed little nuclear localization of NF-kappaB. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKCalpha significantly reduced NF-kappaB activation, ICAM-1 induction, and monocyte adhesion to aorta.


CONCLUSIONS
We conclude that 12/15LO products activate endothelial rhoA and PKCalpha. Activation of rhoA and PKCalpha cause activation and translocation of NF-kappaB 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.
Bolick
David T
DT
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Srinivasan
Suseela
S
Whetzel
Angela
A
Fuller
Lauren C
LC
Hedrick
Catherine C
CC
D000818:Animals; D001011:Aorta / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000172:deficiency*; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D001692:Biological Transport; D002109:Caffeic Acids / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004789:Enzyme Activation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; D002109:Caffeic Acids; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; D018799:Intercellular Adhesion Molecule-1; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D051571:Protein Kinase C-alpha; D020742:rhoA GTP-Binding Protein