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Local microRNA Modulation is a Suitable Way to Prevent In-Stent Restenosis and Coronary Allograft Arteriosclerosis

Wang, Dong1,2,3; Deuse, Tobias1,2,3,4; Stubbendorff, Mandy2,3; Chernogubova, Ekaterina5; Erben, Reinhold G.6; Eken, Suzanne M.5; Jin, Hong5; Heeger, Christian7; Behnisch, Boris8; Reichenspurner, Hermann4; Robbins, Robert C.9; Spin, Joshua M.10; Tsao, Philip S.10; Maegdefessel, Lars5; Schrepfer, Sonja1,2,3

doi: 10.1097/

1TSI-Laboratory, University of California San Francisco, San Francisco, CA, United States; 2TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany; 3Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Reserach), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; 5Department of medicine, Atherosclerosis Reserach Unit, Karolinska Institute, Stockholm, Sweden; 6Universtity of Veterinary Medicine, Universtity of of Veterinary Medicine, Vienna, Austria; 7Department of Cardiology, Asklepios Clinic St. Georg, Hamburg, Germany; 8Translumina GmbH, Translumina GmbH, Hechingen, Germany; 9Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States; 10Veterans Affairs Palo Alto Health Care System and Stanford Cardiocascular Institute, Stanford University, Stanford, CA, United States.

Introduction: Coronary allograft arteriosclerosis is the major cause of organ graft loss after heart transplantation. The underlying pathophysiological process is myointima hyperplasia (MH), which is characterized by augmented vascular smooth muscle cell (SMC) proliferation and migration. MicroRNAs (miRNAs) have been identified as crucial regulators during MH development. Modulation of miRNAs may offer attractive concepts for possible therapeutic interventions. However, since systemic miRNA modulation is feared to cause off-target effects, this would hamper its clinical use. We therefore aimed to locally modulate miRNA expression using coated stents.

Methods: Balloon-injured human internal mammary arteries (IMAs) with or without stent were transplanted into the aortic position of RNU rats. Screening of miRNA candidates associated with vascular (patho)physiology, showed that 7 out of 8 miRNAs were down-regulated and only miR-21 was upregulated. Therefore, therapeutic miR-21 repression was attempted using intravenous application of FAM-tagged-LNA-anti-miR-21 (anti-21) in our humanized MH-model.

Results: Vascular miR-21 expression was suppressed by systemic anti-21 application. This correlated with a reduction of MH-development, luminal obliteration, and vascular SMC proliferation. Systemic anti-21 application did not impede vessel re-endothelialization. However, significant reduction of miR-21 expression in liver, heart, lung, and kidney were observed and serum creatinine was increased. Thus, systemic miRNA modulation caused substantial off-target effects. To minimize off target-effects, anti-21-eluting stents were utilized to suppress miR-21 locally. When compared to bare metal stents, anti-21-coated stents showed decreased in-stent restenosis rate (ISR). No off-target effects were observed with local anti-21 delivery.

Conclusion: In this study, we demonstrated the efficacy of an anti-21-eluting stent for the reduction of ISR by inhibition of smooth muscle cell proliferation without causing off-target effects.

Chrstiane Pahrmann. Claudia Bergow. Hartwig Wieboldt. Martin W. Bergmann. Bernd Zobiak (Umif). Ethicon.

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