Lipoxygenase Products Increase Monocyte Adhesion to Human Aortic Endothelial Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 19; no. 11; pp. 2615 - 2622
• Main Authors: Patricia, Mary Kim, Kim, Jeong A, Harper, Cynthia M, Shih, Peggy T, Berliner, Judith A, Natarajan, Rama, Nadler, Jerry L, Hedrick, Catherine C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.1999; Hagerstown, MD Lippincott
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - biosynthesis; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - pharmacology; Antibodies, Blocking; Antigens, CD - immunology; Antigens, CD - metabolism; Aorta - cytology; Arteriosclerosis - enzymology; Associated diseases and complications; Biological and medical sciences; CD18 Antigens - immunology; CD18 Antigens - metabolism; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cells, Cultured; Diabetes. Impaired glucose tolerance; E-Selectin - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Glucose - pharmacology; Humans; Hydroxyeicosatetraenoic Acids - pharmacology; Hyperglycemia - enzymology; Integrin alpha4; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - metabolism; Lipoxygenase - metabolism; Medical sciences; Monocytes - cytology; Neutrophils - cytology; Neutrophils - drug effects; Vascular Cell Adhesion Molecule-1 - metabolism; Endocrinopathy; Human; Cell culture; Endothelial cell; Biochemical analysis; Monocyte; Enzyme; Immunocytochemistry; Pathogenesis; Diabetes mellitus; Cardiovascular disease; Adhesion; In vitro; HETE; Vascular disease; Pathology; Hyperglycemia; Atherosclerosis; Aorta; Early; Oxidoreductases; Immunofluorescence; Lipoxygenase
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.atv.19.11.2615

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.