Recombinant soluble p-selectin glycoprotein ligand-1-Ig reduces restenosis through inhibition of platelet-neutrophil adhesion after double angioplasty in swine.
BACKGROUND
P-selectin mediates leukocyte recruitment to activated platelets and endothelium through its high-affinity receptor P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte activation and binding have been reported after coronary angioplasty and were correlated with restenosis. We investigated the effect of a recombinant soluble PSGL-1 (rPSGL-Ig) on the adhesion of platelets and neutrophils and the development of restenosis after double arterial injury.


RESULTS
Four weeks after angioplasty of both carotid arteries in pigs, a second angioplasty was performed at the same sites, 15 minutes after a single administration of vehicle or rPSGL-1 (1 mg/kg IV). Animals were euthanized 1 hour, 4 hours, 1 week, or 4 weeks later. Adhesion of autologous (51)Cr-platelets and (111)In-neutrophils was quantified and histological/morphometric analyses were performed. Although rPSGL-Ig did not affect adherence of these cells 1 hour after injury, it significantly reduced the adhesion of platelets (50% at 4 hours and 85% at 1 week) and neutrophils (50% at 4 hours and 78% at 1 week) to deeply injured arteries. At 4 weeks, the residual lumen was 63% larger in rPSGL-Ig-treated arteries as compared with control arteries (6.1+/-0.6 versus 3.8+/-0.1 mm(2); P:<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm(2) in control). The ratio of the external elastic lamina of injured to uninjured reference segments was >1 in treated arteries and <1 in control arteries.


CONCLUSIONS
P-selectin antagonism with rPSGL-Ig inhibits early platelet/leukocyte adhesion on injured arteries and reduces restenosis through a positive impact on vascular remodeling. Hence, rPSGL-Ig may have potential in the prevention of restenosis.
Research Center, Montreal Heart Institute, the University of Montreal, Montreal, Quebec, Canada.
J G
JG
Bienvenu
J F
JF
Tanguay
J F
JF
Théorêt
A
A
Kumar
R G
RG
Schaub
Y
Y
Merhi
D017130:Angioplasty; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D003251:Constriction, Pathologic / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000235:genetics / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D012995:Solubility; D013552:Swine
D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011994:Recombinant Proteins