Prevention of intimal hyperplasia with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in the porcine coronary artery balloon injury model.
OBJECTIVE
The role of P-selectin in the process of restenosis was evaluated using a recombinant immunoglobulin (Ig) chimera form of its ligand, soluble P-selectin glycoprotein ligand-Ig (rPSGL-Ig), as a competitive inhibitor for the natural ligand on leukocytes.


BACKGROUND
Inflammation and coagulation activation after vascular injury may be an important factor in the development of restenosis. P-selectin has been shown to mediate leukocyte-endothelium and leukocyte-platelet interaction. These interactions are mediated through binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) located on the surface of leukocytes.


METHODS
Balloon injury was induced in the left anterior descending and right coronary arteries of 16 pigs at a balloon/artery diameter ratio of 1.5:1. Either rPSGL-Ig (1 mg/kg) or saline was randomly administered 15 min before balloon injury as an intravenous bolus. Four weeks after injury, morphometric analysis, immunohistochemistry and histological evaluation were performed on injured arterial segments.


RESULTS
Increased luminal area was found in the rPSGL-Ig group compared with the placebo group (1.63 +/- 0.57 mm2 vs. 1.26 +/- 0.32 mm2, p = 0.044) owing to significantly reduced neointimal hyperplasia (cross-sectional area, 0.46 +/- 0.45 mm2 vs. 0.13 +/- 0.11 mm2, p = 0.013). Immunohistochemistry and histological evaluation showed a significant decrease in the presence of tumor necrosis factor-alpha, interleukin-1 beta, and infiltration of macrophages in the injured vessel segments in the rPSGL-Ig group.


CONCLUSIONS
P-selectin antagonism using rPSGL-Ig decreases neointimal hyperplasia following balloon injury, by inhibiting the inflammatory and thrombotic responses at the site of balloon injury, which appears to play a pivotal role in the pathogenesis of restenosis.
Wang
K
K
Department of Cardiology, The Cleveland Clinic Foundation, Ohio 44195, USA.
Zhou
Z
Z
Zhou
X
X
Tarakji
K
K
Topol
E J
EJ
Lincoff
A M
AM
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D003327:Coronary Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007136:Immunoglobulins / Q000235:genetics; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D019007:P-Selectin / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D007136:Immunoglobulins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha