Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine

Abstract

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 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 (6.1Ϯ0.6 versus 3.8Ϯ0.1 mm 2 ; PϽ0.002). 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 Ͼ1 in treated arteries and Ͻ1 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.

Single Injection of P-Selectin or P-Selectin Glycoprotein Ligand-1 Monoclonal Antibody Blocks Neointima Formation After Arterial Injury in Apolipoprotein E-Deficient Mice

“…Previous arterial injury studies using pharmacological strategies have not been performed in the setting of hypercholesterolemia and demonstrate a modest benefit on arterial remodeling without a significant reduction in neointima formation. 13 After a single IP injection of the P-selectin antibody RB40.34, flow cytometry data demonstrate that the antibody is available in the serum to bind to activated platelets. In addition, we demonstrate that the mAb remains present for Ն7 days but is no longer detectable at 14 days after administration.…”

“…12 Another group showed that there is a positive effect on remodeling in the pig carotid artery after double injury with administration of recombinant soluble PSGL-1 Ig through inhibition of platelet-neutrophil adhesion in the setting of normal cholesterol levels. 13 We tested the hypothesis that transient P-selectin blockade with a blocking monoclonal antibody (mAb), RB 40.34, or blockade of its ligand, Received December 31, 2002; accepted February 4, 2003. …”

SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery Disease

“…By acting as a counterligand for P-selectin, SELPLG is suspected to be involved in the atherosclerosis process. Several animal studies support this hypothesis: In a cat model, a recombinant soluble form of human SELPLG appeared to protect against myocardial ischemic reperfusion injury (Hayward et al 1999); and in a porcine model, recombinant soluble SELPLG-Ig was shown to have a beneficial effect on restenosis (Bienvenu et al 2001). Animal models have also suggested a key role for SELPLG in thrombogenesis, through its implication in the binding of platelets to neutrophils (Eppihimer & Schaub, 2000;Kumar et al 1999;Wakefield et al 2000).…”

Specific inhibition of P-selectin–mediated cell adhesion by phage display–derived peptide antagonists

“…[9][10][11][12] Studies using P-selectin-deficient mice and P-selectin-specific blocking antibodies have shown that P-selectin participates in the pathophysiology of numerous acute and chronic inflammatory diseases 13,14 including ischemia/reperfusion injury. 15,16 In addition, there is a clear contribution of P-selectin in cardiovascular diseases that have a large inflammatory component such as atherosclerosis, 17,18 restenosis, 19,20 and thrombosis. 21 Evidently, inhibition of Pselectin function would be effective as a therapy in various diseases involving leukocyte adherence to vascular endothelial cells or to platelets.…”