Document Detail

Hemin prevents in-stent stenosis in rat and rabbit models by inducing heme-oxygenase-1.
MedLine Citation:
PMID:  20022212     Owner:  NLM     Status:  MEDLINE    
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.
CONCLUSION: These results suggest that HO-1 is important in limiting in-stent stenosis and can be regarded as a new therapeutic target.
Jean-Marc Hyvelin; Blandine Maurel; Rustem Uzbekov; Roberto Motterlini; Patrick Lermusiaux
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of vascular surgery     Volume:  51     ISSN:  1097-6809     ISO Abbreviation:  J. Vasc. Surg.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-09     Completed Date:  2010-03-04     Revised Date:  2012-10-03    
Medline Journal Info:
Nlm Unique ID:  8407742     Medline TA:  J Vasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  417-28     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
Laboratoire de Physiopathologie de la Paroi Artérielle, EA3852, IFR135, Faculté de Médecine, Université François Rabelais Tours, France.
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MeSH Terms
Angioplasty / adverse effects,  instrumentation*
Apoptosis / drug effects
Arterial Occlusive Diseases / enzymology,  etiology,  pathology,  prevention & control*
Carbon Monoxide / metabolism
Cell Proliferation / drug effects
Constriction, Pathologic
Cyclin-Dependent Kinase Inhibitor Proteins / metabolism
Disease Models, Animal
Drug-Eluting Stents
Endothelium, Vascular / drug effects,  enzymology
Enzyme Induction
Enzyme Inhibitors / pharmacology
Heme Oxygenase (Decyclizing) / antagonists & inhibitors,  biosynthesis*
Hemin / administration & dosage,  pharmacology*
Hypercholesterolemia / complications,  drug therapy,  enzymology
Iliac Artery / drug effects*,  enzymology,  pathology
Injections, Intraperitoneal
Ki-67 Antigen / metabolism
Metalloporphyrins / pharmacology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Muscle, Smooth, Vascular / drug effects,  enzymology
Organometallic Compounds / pharmacology
Prosthesis Design
Protoporphyrins / pharmacology
Rats, Wistar
Time Factors
rhoA GTP-Binding Protein / metabolism
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor Proteins; 0/Enzyme Inhibitors; 0/Ki-67 Antigen; 0/Metalloporphyrins; 0/Metals; 0/Organometallic Compounds; 0/Protoporphyrins; 0/tricarbonylchloro(glycinato)ruthenium(II); 14325-05-4/tin protoporphyrin IX; 16009-13-5/Hemin; 630-08-0/Carbon Monoxide; EC Oxygenase (Decyclizing); EC protein, rat; EC Protein Kinase 1; EC Protein Kinase 3; EC GTP-Binding Protein

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