Abstract
Recent reviews have concluded that although drug eluting stent (DES) are efficient in reducing in stent restenosis, their use does not have a significant effect on overall long-term survival as compared with bare metal stent. DES is associated with delayed vascular wall healing and endothelial function restoration, which mandates longer-term dual antiplatelet therapy. Recent studies demonstrated that the microsatellite polymorphism in the promoter of heme oxygenase-1 (HO-1) gene is related to angiographic restenosis. HO-1 is a rate-limiting enzyme in heme degradation ; leading to the generation of free iron, biliverdin, and carbon monoxide (CO). HO-1 is recognized to offer protection in many cardiovascular disorders. We aim to assess the potential protective effect of hemin, a potent HO-1 inducer, in the development of ISR in both rat and hypercholesterolemic rabbit. In a rat model of aorta stenting and rabbit iliac stenting, chronic treatment with hemin (50 mg/kg/48h/ip) reduced neointima growth (-30 % and -50 % in hemin-treated rats and rabbits respectively), and most importantly stent struts remained covered, contrarily to the use of sirolimus eluting stent. Analysis of the cells facing the arterial lumen (electron microscopy) revealed an ultrastructure similar to endothelial cells and the expression of CD31 (immunogold labeling). Endothelial coverage was similar in hemintreated rats and greater in hemin-treated rabbits when compared to their control groups. Analysis of protein expression, in rats, revealed that hemin, limited the early inflammatory, apoptotic and proliferative cellular events common to ISR. More particularly, hemin treatment was associated with a decrease activity of key regulators of smooth muscle cell migration and proliferation, p42/44, RhoA and an increase of the expression of both cyclin dependent kinase inhibitors, p21 andp27kip1. This beneficial effect of hemin was abolished in presence of SnPP, an inhibitor of HO-1. Finally, CORM-3, a specific carbon monoxide donor, limited ISR. In conclusion, hemin reduced neointima growth without compromising re-endothelialization of the stented arteries. HO-1 plays important role in limiting neointima growth, at least through the production of CO, and can be regarded as a new therapeutic target to prevent ISR.
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