Local MicroRNA Modulation Using a Novel Anti-miR-21–Eluting Stent Effectively Prevents Experimental In-Stent Restenosis

• DOI: 10.1161/atvbaha.115.305597
• Publication Date: 2015-07-17T02:55:22Z
• Authors: Dong Wang; Tobias Deuse; Mandy Stubbendorff; Ekaterina Chernog...; Reinhold G. Erben; Suzanne M. Eken; Hong Jin; Yuhuang Li; Albert Busch; Christian-H. Heeger; Boris Behnisch; Hermann Reichensp...; Robert C. Robbins; Joshua M. Spin; Philip S. Tsao; Sonja Schrepfer; Lars Maegdefessel
• Keywords: Biocompatible; Male; 0301 basic medicine; Nude; Clinical sciences; Cardiorespiratory Medicine and Haematology; Cardiovascular; Muscle, Smooth, Vascular; Graft Occlusion; Coated Materials, Biocompatible; Cardiovascular Medicine and Haematology; Antinuclear; Scanning; Assistive Technology; Microscopy; Graft Occlusion, Vascular; hyperplasia; Drug-Eluting Stents; Middle Aged; Coronary Vessels; microRNAs; 3. Good health; Heart Disease; 5.1 Pharmaceuticals; stents; Antibodies, Antinuclear; Muscle; Female; Smooth; Development of treatments and therapeutic interventions; Biotechnology; Clinical Sciences; Bioengineering; Prosthesis Design; Electron; Cardiovascular medicine and haematology; Antibodies; Coronary Restenosis; 03 medical and health sciences; Vascular; coronary restenosis; Neointima; Animals; Humans; Heart Disease - Coronary Heart Disease; Cell Proliferation; Biomedical and Clinical Sciences; Animal; Coated Materials; Atherosclerosis; Rats; rats; Disease Models, Animal; MicroRNAs; Cardiovascular System & Hematology; Gene Expression Regulation; Disease Models; Microscopy, Electron, Scanning

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.