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. A key early event in atherosclerosis development is the interaction of monocytes and endothelial cells in the vessel wall. 1 Activated monocytes interact with selectins, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cell surface to roll along and firmly adhere to the endothelium. 2,3 Monocytes are the primary inflammatory cells localized to human atherosclerotic plaques and play a major role in atherosclerotic plaque progression. 4 The apolipoprotein E-deficient mouse (apoEKO) is a well-characterized model of atherosclerosis that develops extensive aortic and coronary atherosclerosis and severe hypercholesterolemia when fed a Western-type diet. 5,6 Studies have reported increased Pselectin-mediated and VCAM-1-mediated monocyte rolling along apoE-deficient mouse endothelium, 7,8 and have illustrated that VCAM-1 and ICAM-1 are critical for atherosclerosis development in apoEKO mice. 9,10 See page 1204 12/15 lipoxygenase (12/15LO) incorporates molecular oxygen in a stereo-specific manner into arachidonic and linoleic acids to generate 12-S-and 15-S-hydroxyeicosatetraenoic acids (12SHETE/15SHETE) and 13-Shydroxyoctadecadienoic acid (13SHODE), respectively. 11,12 Sources of 12/15LO eicosanoids in vascular cells are endothelial cells, smooth muscle cells, monocytes, and platelets. 13 Several groups have shown that the human 12/15LO enzyme oxidizes low-density lipoprotein (LDL) in vitro, and that 12/15LO inhibitors decrease the ability of macrophages to oxidize LDL. 14 -17 12/15LO protein has been localized to aortic atherosclerotic lesions in rabbits and in humans. 18,19 We have shown that activated human endothelial cells (ECs) have increased expression of 12/ 15LO protein that mediates monocyte adhesion. 20 We have also shown that exogenous addition of 12SHETE and 15SHETE to EC significantly ...