Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1.
The binding of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) to platelet P-selectin is central to post-angioplasty restenosis. Although intracoronary stents limit the mechanical component of restenosis, they cause marked thrombo-inflammation and neointimal proliferation leading to greater late luminal loss. We sought to demonstrate that P-selectin antagonism, using recombinant PSGL-1 (rPSGL-Ig), is effective in reducing platelet-leukocyte reactions and in-stent restenosis in double-injured porcine coronary arteries. Two weeks after initial injury by angioplasty to the coronary arteries, stents were implanted at the injury-induced lesion site, 15 min after an i.v. bolus administration of a vehicle or rPSGL-Ig (1 mg/kg). Four weeks later, adhesion of (51)Cr-platelets and (111)In-neutrophils and histomorphometric analyses were performed. In-stent residual lumen was almost 3 fold larger in rPSGL-Ig-treated arteries (3.1 +/- 0.4 mm(2)) as compared to control (1.1 +/- 0.2 mm(2)), which correspond to 64% vascular stenosis in control with no change in rPSGL-Ig animals. For a similar injury score, in-stent neointima was significantly reduced by 30 to 40% in the rPSGL-Ig group and quantitative coronary angiography showed a significant 35% reduction in late lumen loss. These effects of rPSGL-Ig were associated with a respective 70% and 53% reduction in platelet and neutrophil adhesion. In conclusion, pretreatment with rPSGL-Ig reduces thrombo-inflammatory responses, neointimal proliferation, and in-stent restenosis. P-selectin antagonism offers a promising therapy to improve clinical outcomes of coronary stenting.
Tanguay
Jean-François
JF
Research Center, Montreal Heart Institute, and University of Montreal, Quebec, Canada.
Geoffroy
Pascale
P
Sirois
Martin G
MG
Libersan
Danielle
D
Kumar
Anjali
A
Schaub
Robert G
RG
Merhi
Yahye
Y
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D001792:Blood Platelets / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D023903:Coronary Restenosis / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D007962:Leukocytes / Q000473:pathology; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D011994:Recombinant Proteins; D015607:Stents / Q000009:adverse effects*; D013552:Swine; D013927:Thrombosis / Q000517:prevention & control
D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011994:Recombinant Proteins