Hemin prevents in-stent stenosis in rat and rabbit models by inducing heme-oxygenase-1

ObjectiveThe introduction of drug-eluting stents (DES) has largely added benefit to the percutaneous coronary intervention. Questions about the long-term safety of DES have been raised, however, particularly with respect to late stent thrombosis. Research efforts are now being directed toward therapeutics that can impede smooth muscle proliferation and promote vascular healing. Emerging data suggest that heme oxygenase-1 (HO-1), an inducible oxidoreductase enzyme system, can exert cytoprotective effects on endothelial cells and limit smooth muscle cell proliferation. We assessed the ability of hemin, a potent HO-1 inducer, to reduce in-stent stenosis without compromising re-endothelialization.MethodsRat aorta and rabbit iliac arteries were stented. Animals received ongoing treated with intraperitoneal hemin (50 mg/kg) or vehicle. At 7 to 28 days after surgery, stented arterial segments were collected and processed for histologic, electron microscopy, or protein analysis.ResultsIn both models, treatment with hemin reduced neointima growth without compromising re-endothelialization of the stented arteries. In the rat aorta, analysis of protein expression at 7 and 28 days after stenting revealed that hemin increased HO-1 expression and limited the early inflammatory, apoptotic, and proliferative cellular events that are common to in-stent stenosis. Hemin treatment decreased the expression of the Ki-67 protein and the activity of key regulators of smooth muscle cell proliferation, including p42/44, RhoA, and up-regulated the expression of cyclin-dependent kinase inhibitors. The beneficial effects of hemin were abolished in the presence of tin-protoporphyrin IX, an HO inhibitor. Finally, treatment with tricarbonylchloro(glycinato)ruthenium(II), a carbon monoxide donor, reduced in-stent stenosis in the rat aorta, suggesting that carbon monoxide, a by-product of heme degradation, might contribute to the protective effect of hemin.ConclusionThese results suggest that HO-1 is important in limiting in-stent stenosis and can be regarded as a new therapeutic target.

Clinical RelevanceLong-term outcomes of endovascular treatments have not been impressive due to vascular stenosis caused mainly by intimal hyperplasia. Questions have been raised about the long-term safety of drug-eluting stents, particularly with respect to late stent thrombosis. Accumulating data indicate a link between inflammation and in-stent stenosis as well as between delayed endothelialization and thrombosis. We demonstrated in an animal model that hemin, a compound used in the management of porphyria, induced heme oxygenase-1 and limited inflammation and in-stent restenosis without compromising endothelialization. Thus, heme oxygenase-1 may be considered as a novel target in the next generation of drug-eluting stents for preventing in-stent restenosis after endovascular therapies.