TY - JOUR
T1 - Local MicroRNA modulation using a novel Anti-MIR-21-eluting stent effectively prevents experimental in-stent restenosis
AU - Wang, Dong
AU - Deuse, Tobias
AU - Stubbendorff, Mandy
AU - Chernogubova, Ekaterina
AU - Erben, Reinhold G.
AU - Eken, Suzanne M.
AU - Jin, Hong
AU - Li, Yuhuang
AU - Busch, Albert
AU - Heeger, Christian H.
AU - Behnisch, Boris
AU - Reichenspurner, Hermann
AU - Robbins, Robert C.
AU - Spin, Joshua M.
AU - Tsao, Philip S.
AU - Schrepfer, Sonja
AU - Maegdefessel, Lars
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/9/28
Y1 - 2015/9/28
N2 - 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.
AB - 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.
KW - coronary restenosis
KW - hyperplasia
KW - microRNAs
KW - rats
KW - stents
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U2 - 10.1161/ATVBAHA.115.305597
DO - 10.1161/ATVBAHA.115.305597
M3 - Article
C2 - 26183619
AN - SCOPUS:84940398432
SN - 1079-5642
VL - 35
SP - 1945
EP - 1953
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 9
ER -