Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor.
BACKGROUND
Chronic inflammation is a characteristic feature of abdominal aortic aneurysms (AAAs), but the molecular signals responsible for recruiting monocytes into the outer aortic wall are unresolved. The purpose of this study was to examine whether AAA tissues elaborate chemotactic activity for mononuclear phagocytes and to determine whether this activity is attributable to interactions between elastin degradation peptides (EDPs) and their cell surface receptor, the 67-kD elastin binding protein (EBP).


METHODS
Soluble proteins were extracted from human AAA tissues, and chemotactic activity for differentiated U937 mononuclear phagocytes was measured by use of a modified Boyden chamber. Chemotactic activity induced by N -formyl-Met-Leu-Phe was used as a positive control and checkerboard analysis was used to distinguish chemotaxis from chemokinesis. Inhibition of chemotaxis was tested by peptide competition, blocking antibodies and galactosugar-mediated dissociation of the 67-kD EBP.


RESULTS
AAA extracts stimulated a concentration-dependent increase in monocyte migration that reached up to 24% of the maximal effect induced by N -formyl-Met-Leu-Phe. Checkerboard analysis demonstrated that AAA extracts stimulated chemotaxis without a chemokinetic effect. AAA-derived chemotactic activity was eliminated by competition with Val-Gly-Val-Arg-Pro-Gly (VGVAPG), a repetitive peptide found in human elastin that binds to cellular elastin receptors, and decreased nearly 40% in the presence of BA-4, an antielastin monoclonal antibody that can block EDP-mediated chemotactic activity. Monocyte chemotaxis in response to both VGVAPG and AAA extracts was abolished in the presence of lactose, a galactosugar that specifically dissociates the 67-kD EBP, but it was unaffected by either glucose, fructose, or mannose.


CONCLUSIONS
These findings indicate that soluble EDPs released within human AAA tissue can subsequently attract mononuclear phagocytes through ligand-receptor interactions with the 67-kD EBP, thereby providing a plausible molecular mechanism to explain the inflammatory response that accompanies aneurysmal degeneration. Better understanding of factors regulating inflammatory cell recruitment may lead to novel forms of therapy for early stages of aneurysmal degeneration.
Hance
Kirk A
KA
Department of Surgery (Section of Vascular Surgery), Washington University School of Medicine, St Louis, MO 63110, USA.
Tataria
Monika
M
Ziporin
Scott J
SJ
Lee
Jason K
JK
Thompson
Robert W
RW
D000906:Antibodies / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000503:physiopathology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004549:Elastin / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology
D000906:Antibodies; D007074:Immunoglobulin G; D009842:Oligopeptides; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004549:Elastin; C042635:valyl-glycyl-valyl-alanyl-prolyl-glycine