title: Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells.
abstract: The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key initial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucose medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte adhesion 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)-hydroxyeicosatetraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultured 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 26+/-1 monocytes per field, respectively, P<0.001). Expression of the adhesion molecules vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1 was not significantly increased. However, both glucose 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 intercellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively demonstrate for the first time in HAECs that the 12-LO pathway can induce monocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results suggest that the 12-LO pathway may play a role in the increased susceptibility of diabetics to atherosclerosis.
authors.affiliation: Division of Cardiology, University of California at Los Angeles, 90095-1679, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Patricia
authors.forename: J A
authors.initials: JA
authors.lastname: Kim
authors.forename: C M
authors.initials: CM
authors.lastname: Harper
authors.forename: P T
authors.initials: PT
authors.lastname: Shih
authors.forename: J A
authors.initials: JA
authors.lastname: Berliner
authors.forename: R
authors.initials: R
authors.lastname: Natarajan
authors.forename: J L
authors.initials: JL
authors.lastname: Nadler
authors.forename: C C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis / Q000494:pharmacology; D019138:Antibodies, Blocking; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000201:enzymology; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D006943:Hyperglycemia / Q000201:enzymology; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D018821:CD18 Antigens; D019040:E-Selectin; D006893:Hydroxyeicosatetraenoic Acids; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D008084:Lipoxygenase; D005947:Glucose