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


METHODS
Rat 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.


RESULTS
In 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.


CONCLUSIONS
These results suggest that HO-1 is important in limiting in-stent stenosis and can be regarded as a new therapeutic target.
Hyvelin
Jean-Marc
JM
Laboratoire de Physiopathologie de la Paroi Artérielle, EA3852, IFR135, Faculté de Médecine, Université François Rabelais Tours, France. hyvelin.jean-marc@neuf.fr
Maurel
Blandine
B
Uzbekov
Rustem
R
Motterlini
Roberto
R
Lermusiaux
Patrick
P
D017130:Angioplasty / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002248:Carbon Monoxide / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003251:Constriction, Pathologic; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006427:Hemin / Q000008:administration & dosage / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D007083:Iliac Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008670:Metals; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009942:Organometallic Compounds / Q000494:pharmacology; D011474:Prosthesis Design; D011524:Protoporphyrins / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015607:Stents; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D008665:Metalloporphyrins; D008670:Metals; D009942:Organometallic Compounds; D011524:Protoporphyrins; C476530:tricarbonylchloro(glycinato)ruthenium(II); D006427:Hemin; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein