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EXPERIMENTAL STUDY

Prevention of intimal hyperplasia with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in the porcine coronary artery balloon injury model

^a Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Manuscript received December 22, 2000; revised manuscript received April 5, 2001, accepted April 11, 2001.

Reprint requests and correspondence: Dr. A. Michael Lincoff, Cardiology Department, The Cleveland Clinic Foundation, 9500 Euclid Ave., F25, Cleveland, Ohio 44195
lincofa{at}ccf.org

OBJECTIVES

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-Lg 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.

Abbreviations and Acronyms   BSA = bovine serum albumin   FL = fracture length   IA/FL = ratio of neointimal area/fracture length of the internal elastic lamina   IEL = internal elastic lamina   IL-1 beta = interleukin-1 beta   IV = intravenous   LAD = left anterior descending coronary artery   NO = nitric oxide   PBS = phosphate-buffered saline   PCNA = proliferating cell nuclear antigen   PSGL-1 = P-selectin glycoprotein ligand-1   RCA = right coronary artery   rPSGL-Ig = recombinant P-selectin glycoprotein ligand-immunoglobulin   SMC = smooth muscle cell   TNF-alpha = tumor necrosis factor-alpha

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