Circulating microRNA-122-5p is associated with a lack of improvement in left-ventricular function after TAVR and regulates viability of cardiomyocytes via extracellular vesicles

Abstract Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for high- and intermediate-risk patients with severe symptomatic stenosis (AVS). However, specific role circulating microRNAs (miRNAs) in the improvement of cardiac function after TAVR has not yet been investigated. Herein, we profiled differential expression miRNAs extracellular vesicles (EV-miRNAs) and, particular, novel miR-122-5p cardiomyocytes. Circulating EV-associated were investigated by using an unbiased Taqman-based human miR array. Several EV-miRNAs (miR-122-5p, miR-26a, miR-192, miR-483-5p, miR-720, miR-885-5p, miR-1274) significantly deregulated at day seven comparison to pre-procedural levels without LVEF-improvement. The higher negatively correlated LVEF both (r=−0.264 p=0.015) six months (r=−0.328 p=0.0018) TAVR. At three-year follow-up, level displayed increased cardiovascular mortality (p=0.03). By utilization patient-derived samples murine aortic-stenosis model, observed that correlates function, which associated LVEF. Graded wire-injury-induced aortic-valve-stenotic mice demonstrated miR-122-5p, was related cardiomyocytes dysfunction. Murine ex vivo experiments revealed highly enriched endothelial cells Gain- loss-of-function suggested EV-mediated shuttling increases recipient regulates viability Mechanistically, pulldown, electrophoretic mobility shift assay, RNA immunoprecipitation confirmed interacts RNA-binding protein, hnRNPU, sequence-specific manner encapsulate into large EVs. Upon cells, reduces anti-apoptotic gene BCL2, binding its 3' untranslated region inhibit translation, thereby decreasing target Increased pro-apoptotic EV-incorporated are reduced Extracellular vesicular apoptosis BCL2-dependent manner. Funding Acknowledgement Type funding sources: Public hospital(s). Main source(s): German Research Foundation (DFG)German Society Cardiology (DGK)