Abstract
Background: Inflammatory mechanisms, which can be affected by altered metabolic profiles such as hypercholesterolemia (HC), contribute to the pathophysiology of in-stent restenosis (ISR). CD47 is a transmembrane protein that is known to inhibit immune cell and platelet activation. Previously in a rat model, we showed that immobilizing peptide sequences of CD47 (pepCD47) to stainless steel (SS) stent surfaces decreased platelet and leukocyte association, and significantly reduced ISR. In these current studies, we use HC rabbits to test the hypothesis that the pepCD47-modified stents will reduce ISR in a pro-atherogenic phenotype. Methods: PepCD47 was attached to SS using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. Bare metal (BM) and pepCD47 SS foils (n=6) were exposed to anticoagulated blood from normocholesterolemic (NC) or HC rabbits for 1 hr. The relative abundance of the surface-associated cells was determined fluorimetrically. Rabbits (n=4) were fed a HC diet for 4 weeks prior to placing BMS or pepCD47 stents bilaterally in the iliac locations. The diet was continued until sacrifice (4 weeks). After chemical dissolution of the stent struts, the segments were paraffin embedded, sectioned, stained and assessed morphometrically. The prevalence of peri-strut macrophages was determined by immunohistochemistry (IHC) as a percentage of a strut circumference infiltrated with macrophages. Results: An 8% decrease of platelet and leukocyte attachment to a pepCD47-derivatized SS compared to BM foils (p=NS) was observed with NC blood, while a significant 35% decrease of cell attachment (p<0.002) was found between the pepCD47 and BM foils exposed to HC rabbit blood. Lumen area increased (25%) whereas the neointimal area, % stenosis and neointima to media ratio decreased (23%, 25%, and 25% p=0.04, respectively) in the arteries treated with pepCD47 stents compared to BMS controls. IHC showed a 34% reduction of macrophage infiltration in the peri-strut area (p=0.048). Conclusion: These results are the first to show the anti-restenotic properties of pepCD47 modified stents in a translational HC rabbit model. The anti-restenotic effects are likely due to CD47-mediated reduction of stent-triggered inflammation.
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