The role of endothelial cell adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 in leucocyte recruitment induced by exogenous methylglyoxal.
Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In hyperglycaemic conditions, increased MG level has been linked to the development of diabetes and its vascular complications at the macrovascular and microvascular levels where inflammation plays a role. To study the mechanism of MG-induced inflammation in vivo, we applied MG locally to healthy mice and used intravital microscopy to investigate the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in cremasteric microvasculature. Administration of MG (25 and 50 mg/kg) to the tissue dose-dependently induced leucocyte recruitment at 4.0-5.5 hr, with 84-92% recruited cells being neutrophils. Such MG treatment up-regulated the expression of endothelial cell adhesion molecules P-selectin, E-selectin, intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1. Activation of the nuclear factor-κB signalling pathway contributed to MG-induced up-regulation of these adhesion molecules and leucocyte recruitment. The role of the up-regulated endothelial cell adhesion molecules in MG-induced leucocyte recruitment was determined by applying specific functional blocking antibodies to MG-treated animals and observing changes in leucocyte recruitment parameters. Our data demonstrate that the up-regulation of P-selectin, E-selectin and intercellular adhesion molecule-1 contributes to the increased leucocyte rolling flux, reduced leucocyte rolling velocity, and increased leucocyte adhesion, respectively. Our results reveal the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in microvasculature, an inflammatory condition related to diabetic vascular complications.
Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Yang
Y
Su
Xi
X
Lei
Lingyun
L
Wu
Lixin
L
Liu
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D002448:Cell Adhesion; D002460:Cell Line; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000187:drug effects / Q000276:immunology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D019138:Antibodies, Blocking; D019040:E-Selectin; D016328:NF-kappa B; D009570:Nitriles; D019007:P-Selectin; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D011765:Pyruvaldehyde