Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells

The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key init ial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucos e medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte a dhesion to HAECs under hyperglycemic conditions is via the 12-lipoxygenase (12-LO) pathway. In this study, we demonstrated in HAECs that the major LO metabolite of arachidonic acid was the 12-LO product, 12(S)-hydroxyei-cosat etraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultu red under high-glucose conditions. Furthermore, treatment of HAECs with 12( S)-HETE induced monocyte, but not neutrophil, adhesion an average of 3-fold (range of 1.5- to 5-fold) compared with untreated cells (75 +/- 5 versus 2 6 +/- 1 monocytes per field, respectively, P < 0.001). Expression of the ad hesion molecules vascular cell adhesion molecule-1, E-selectin, and interce llular adhesion molecule-1 was not significantly increased. However, both g lucose and 12(S)-HETE induced a 60% increase in HAEC surface expression of connecting segment-1 (ie, CS-1) fibronectin, a ligand for very late-acting antigen-4 (VLA-4). The antibodies used to block monocyte integrin VLA-4 and leukocyte function-related antigen-1, a monocytic counterreceptor for inte rcellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively d emonstrate for the first time in HAECs that the 12-LO pathway can induce mo nocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results sugge st that the 12-LO pathway may play a role in the increased susceptibility o f diabetics to atherosclerosis.