Molecular determinants of oxidized low-density lipoprotein-induced leukocyte adhesion and microvascular dysfunction.
Oxidized low-density lipoproteins (oxLDL) have been implicated in the leukocyte recruitment and microvascular dysfunction associated with atherosclerosis. The objectives of this study were to define the adhesion molecules that mediate oxLDL-induced leukocyte-endothelial cell adhesion and to determine whether leukocyte-endothelial cell adhesion contributes to the endothelial barrier dysfunction elicited by oxLDL. Leukocyte-endothelial cell adhesion and emigration, albumin extravasation, and mast cell degranulation were monitored in rat mesentery in response to native LDL (nLDL) or copper-oxidized LDL (oxLDL). Intra-arterial infusion of oxLDL but not nLDL elicited increases in leukocyte adherence and emigration, mast cell degranulation, and albumin leakage. The oxLDL-induced leukocyte adherence/emigration was attenuated by pretreatment with monoclonal antibodies directed against CD11/CD18, intercellular adhesion molecule-1, P-selectin, and L-selectin but not by pretreatment with a nonbinding monoclonal antibody. The albumin leakage and mast cell degranulation responses were attenuated by all of the same monoclonal antibodies except L-selectin. In addition, a peptide previously shown to inhibit leukocyte-endothelial cell adhesion in vitro also attenuated leukocyte adherence and mast cell degranulation in this model. These findings implicate CD11/ CD18, L-selectin, intercellular adhesion molecule-1, and P-selectin in the leukocyte recruitment elicited by oxLDL and invoke a role for adherent leukocytes in the accompanying increase in mast cell degranulation and albumin leakage.
Liao
L
L
Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Starzyk
R M
RM
Granger
D N
DN
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000473:pathology*; D008833:Microcirculation / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019087:Selectins / Q000502:physiology
D008077:Lipoproteins, LDL; D019087:Selectins; C099252:oxidized low density lipoprotein