期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 35, 期 9, 页码 1945-1953出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.115.305597
关键词
coronary restenosis; hyperplasia; microRNAs; rats; stents
资金
- Cardiovascular Research Center (CVRC) at the University Medical Center Hamburg-Eppendorf
- German Center for Cardiovascular Research (DZHK)
- Else-Kroner-Fresenius-Stiftung [2012_EKES.04]
- National Institutes of Health [1HL-105299, 1HL122939]
- Fondation Leducq [CDA 2013-2015]
- Deutsche Forschungsgemeinschaft (DFG) [SCHR992/3-1, SCHR992/4-1]
- Karolinska Institute Cardiovascular Program Career Development Grant
- Swedish Heart-Lung-Foundation [20120615, 20130664, 20140186]
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.
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