P311The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation after arterial injury without impairing re-endothelialisation

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Abstract

Purpose

The chemokine receptor CXCR4 (CXC motif receptor 4) is crucial in neointima formation which is problematic in restenosis after stent implantation. Drug-eluting stents (e.g., coated with sirolimus) have reduced the risk of restenosis but delayed re-endothelialisation promotes late stent thrombosis. We compared CXCR4 antagonism with sirolimus treatment in preventing neointima formation after arterial injury in mice.

Methods

Apolipoprotein E-/- mice on high fat diet were treated with a CXCR4 antagonist (POL5551 (POL), a Protein Epitope Mimetic (PEM)) or sirolimus after carotid wire injury (n=6-8 per group). The drugs were administered continuously via osmotic pumps (POL: 2 and 20 mg/kg/d; sirolimus: 1.25 mg/kg/d) for 28 days. The neointimal area, smooth muscle cell (SMC) content, macrophage content, collagen content and endothelial coverage were quantified by planimetry of histological sections from injured arteries stained with Elastica van Giesson, or after immunostaining for α-smooth muscle actin, Mac-2, Collagen type I and von Willebrand Factor, respectively. Peripheral Sca-1 + /Lin- smooth muscle progenitor cells (SPCs) were measured by flow cytometry.

Results

Sirolimus as well as high and low dose of POL greatly reduced the neointimal area compared to corresponding vehicle (69%, 70% and 63%, respectively). High dose POL for just 3 days did not affect the neointimal area. The neointimal macrophage content markedly increased by sirolimus application (70%). The macrophage content decreased by high dose (57%), but not by low dose, POL application. Sirolimus and high dose POL highly diminished the neointimal SMC content (69% and 85%, respectively), while low dose POL did not. Increase of SPCs in the circulation 1 day after injury was prevented in mice given sirolimus and high dose POL, but not in mice given low dose POL. The neointimal collagen content was diminished by low dose (41%), but not by high dose, POL treatment. In all groups, there were no significant changes in the neointimal neutrophil content as well as in the serum levels of ALT, creatinine, troponin T, cholesterol and triglycerides. The endothelial coverage of plaques was not reduced by POL, but significantly reduced by sirolimus (14%).

Conclusions

CXCR4 antagonism by POL5551 is equally effective as sirolimus treatment in reducing neointima formation after arterial injury in mice. It might be more beneficial than sirolimus because it leads to a more stable plaque phenotype and, of note, does not impair re-endothelialisation. These results indicate that POL5551 might be a promising alternative drug for the coating of stents.

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