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A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis
Published on: May 14, 2013
Local MicroRNA Modulation Using a Novel Anti-miR-21-Eluting Stent Effectively Prevents Experimental In-Stent
Dong Wang1, Tobias Deuse1, Mandy Stubbendorff1
1From the Department of Cardiovascular Surgery, TSI-Laboratory (D.W., T.D., M.S., S.S.) and Department of Cardiovascular Surgery (T.D., H.R.), University Heart Center Hamburg, Hamburg, Germany; Department of Cardiovascular Surgery, Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (D.W., T.D., M.S., S.S.); Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, CMM L8:03, Stockholm, Sweden (E.C., S.M.E., H.J., Y.L., A.B., L.M.); Unit of Physiology, Pathophysiology, and Experimental Endocrinology, University of Veterinary Medicine, Vienna, Austria (R.G.E.); Department of Cardiology Asklepios Clinic St. Georg, Hamburg, Germany (C.-H.H.); Translumina GmbH, Hechingen, Germany (B.B.); Department of Cardiothoracic Surgery, Stanford Cardiovascular Institute, Stanford University, CA (R.C.R., S.S.); Department of Cardiovascular Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA (J.M.S., P.S.T.); and Department of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University, CA (J.M.S., P.S.T.).
Objective:
Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) because of myointimal hyperplasia remains a major complication.
Approach And Results:
We investigated the regulatory role of microRNAs in myointimal hyperplasia/ISR, using a humanized animal model in which balloon-injured human internal mammary arteries with or without stenting were transplanted into Rowett nude rats, followed by microRNA profiling. miR-21 was the only significantly upregulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared with coronary artery disease specimen. We systemically repressed miR-21 via intravenous fluorescein-tagged-locked nucleic acid-anti-miR-21 (anti-21) in our humanized myointimal hyperplasia model. As expected, suppression of vascular miR-21 correlated dose dependently with reduced luminal obliteration. Furthermore, anti-21 did not impede reendothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increase in serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21-coated stents. Compared with bare-metal stents, anti-21-coated stents effectively reduced ISR, whereas no significant off-target effects could be observed.
Conclusion:
This study demonstrates the efficacy of an anti-miR-coated stent for the reduction of ISR.
Insights
In-stent restenosis (ISR) is a complication of vascular interventions. Local suppression of miR-21 using anti-miR-coated stents effectively reduced ISR without systemic side effects.
Area of Science:
- Vascular biology
- Molecular medicine
- Biotechnology
Background:
- In-stent restenosis (ISR) is a significant complication following vascular interventions, primarily driven by myointimal hyperplasia.
- Current stent technologies still face challenges in preventing ISR.
- MicroRNAs (miRNAs) are implicated in the pathogenesis of myointimal hyperplasia and ISR.
Purpose of the Study:
- To investigate the role of microRNAs in myointimal hyperplasia and ISR.
- To evaluate the therapeutic potential of targeting miR-21 for ISR reduction.
- To compare systemic versus local delivery of anti-miR therapy for ISR.
Main Methods:
- A humanized animal model involving transplanted balloon-injured human internal mammary arteries in Rowett nude rats was utilized.
- MicroRNA profiling identified miR-21 as upregulated in ISR.
- Systemic and local (anti-miR-coated stent) delivery of anti-miR-21 was assessed.
Main Results:
- miR-21 was significantly upregulated in human ISR tissues and the animal model.
- Systemic anti-miR-21 reduced ISR but caused off-target effects in multiple organs.
- Anti-miR-21-coated stents effectively reduced ISR with no observed off-target effects.
Conclusions:
- miR-21 plays a crucial role in the development of in-stent restenosis.
- Anti-miR-coated stents represent a promising localized therapeutic strategy for reducing ISR.
- Local delivery of anti-miRs avoids systemic toxicity associated with broader suppression.
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