(Circulation. 2001;103:1128.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine
From the Research Center, Montreal Heart Institute (J.-G.B., J.-F. Tanguay, J-F. Théorêt, Y.M.), the University of Montreal (J.-G.B., J.-F. Tanguay, J-F. Théorêt, Y.M.), Montreal, Quebec, Canada; and Wyeth/Genetics Institute (A.K., R.G.S.), Andover, Mass.
Correspondence to Yahye Merhi, Laboratory of Experimental Pathology, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada, H1T 1C8. E-mail merhi{at}icm.umontreal.ca
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.
Methods and 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 51Cr-platelets and 111In-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 mm2; P<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm2 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.
Key Words: restenosis • remodeling • glycoproteins • platelets • leukocytes
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