Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide

Recent evidence indicates that chronic hyperhomocysteinemia, which is found in from 9 to 15% of the general population, is an independent risk factor for the development of atherosclerosis. We sought to elucidate the mechanis m by which exposure of the vascular wall to high levels of homocysteine ini tiates this inflammatory reaction. We examined the acute effect of homocyst eine on endothelial dysfunction in isolated rat arteries and on microcircul atory leukocyte-endothelium interaction in vivo. Intravital microscopy of r at mesenteric venules was performed by superfusing the mesentery with incre asing concentrations of homocysteine (1-5 mmol/l). There was a significant concentration- and time-dependent increase in leukocyte rolling, adherence, and extravasation compared with control rats superfused with Krebs Hensele it solution (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly increased P-selectin and intercellular adhesion molecule-1 ( ICAM-1) expression on intestinal venules after homocysteine superfusion. In contrast, mesenteric superfusion with the nitric oxide donor 4-hydroxymeth yl-furazan-3-carboxylic acid oxide (CAS1609, 1 mu mol/l) significantly atte nuated homocysteine-induced leukocyte rolling, adherence, and transmigratio n to control levels (p < 0.01). CAS1609 also attenuated both P-selectin and ICAM 1 expression on mesenteric venules and decreased CD18 expression on i solated leukocytes. Superior mesenteric arteries incubated with 5 mmol/l ho mocysteine developed significant (p < 0.01) endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent dilators). Acute hyperhomocyst einemia induces endothelial dysfunction, characterized by a loss of endothe lium-derived nitric oxide, leading to an inflammatory state. This state res ults in increased leukocyte rolling, adherence, and transmigration by upreg ulation of cell adhesion molecules. Our data suggest that hyperhomocysteine mia inhibits the important homeostatic role of nitric oxide in preventing e ndothelial dysfunction. (C) 2000 Elsevier Science Inc. All rights reserved.