Hypercholesterolemia aggravates in-stent restenosis in rabbits: a mitigating effect of stent surface modification with CD47-derived peptide

BackgroundHypercholesterolemia (HC) has previously been shown to augment restenotic response in several animal models and humans. However, the mechanistic aspects of in-stent restenosis (ISR) on a hypercholesterolemic background, including potential augmentation of systemic and local inflammation precipitated by HC are not completely understood. CD47 is a transmembrane protein known to abort crucial inflammatory pathways. Our present studies have examined the interrelation between HC, inflammation, and ISR and investigated the therapeutic potential of stents coated with a CD47-derived peptide (pepCD47) in the hypercholesterolemic rabbit model. Methods and ResultsPepCD47 was immobilized on metal foil coupons and stents using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. The relative abundance of the surface-associated cells on bare metal (BM) and pepCD47 foils exposed to whole rabbit blood showed a 40% inhibition of cell attachment on pepCD47-modified surfaces. Likewise, cytokine expression analyzed in buffy coat-derived cells cultured over the BM and pepCD47-derivatized foils demonstrated a M2/M1 increase with pepCD47 coating. Hypercholesterolemic and normocholesterolemic rabbit cohorts underwent bilateral implantation of BM and pepCD47 stents in the iliac location. Hypercholesterolemia increased neointimal growth in comparison with normocholesterolemic animals at 4 weeks post-stenting. These untoward outcomes were mitigated in the arteries of hypercholesterolemic rabbits treated with pepCD47-derivatized stents. Compared to NC animals, inflammatory cytokine immunopositivity and macrophage infiltration of peri-strut areas increased in HC group animals, and was attenuated in the arteries of hypercholesterolemic rabbits treated with pepCD47 stents. ConclusionsAugmented inflammatory responses triggered by HC underlie severe ISR morphology in hypercholesterolemic rabbits. Blockage of initial platelet and leukocyte attachment to stent struts through CD47 functionalization of stents mitigates pro-restenotic effects of HC.