Abstract 553: Inhibition of Microrna-21 Prevents Myocardial Remodelling and Dysfunction in a Pig Model of Ischemia/reperfusion Injury

Background: Upregulation of microRNA-21 (miR-21) has been associated with myocardial disease and its systemic inhibition was effective in reducing cardiac fibrosis and dysfunction in rodent models. However, the translation to human disease is challenging, as systemic application of miR inhibitors does not achieve adequate delivery in most organs including the heart. Here, we sought to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a large animal model of heart failure. Methods and results: Pigs underwent percutaneous occlusion of the left coronary artery for 60 minutes and were followed up for 33 days. A synthetic inhibitor against miR-21 (LNA-antimiR-21, 10 mg per application) was applied locally by intracoronary infusion at days 5 and 19 after the injury. AntimiR-21 effectively suppressed the I/R-induced increase of miR-21. At 33 days after I/R, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy, and improved cardiac function (ejection fraction: I/R control 22±1% vs. I/R LNA-21 33±2%). RNA sequencing of ischemic myocardium revealed a significant enrichment for miR-21 targets in anti-miR-21 treated hearts. Mechanistically, antimiR-21 interfered with a number of signalling pathways involved in myocardial remodelling including the MAPK-ERK signalling cascade. Conclusion: Taken together, our study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of myocardial ischemia. AntimiR-21 prevented the structural and functional consequences of ischemic myocardial damage.