A three-step approach identifies novel shear stress-sensitive endothelial microRNAs involved in vasculoprotective effects of high-intensity interval training (HIIT)

// Boris Schmitz 1 , * , Franziska L. Breulmann 1 , * , Bothaynah Jubran 2 , Florian Rolfes 1 , Lothar Thorwesten 1 , Michael Krüger 3 , Andreas Klose 3 , Hans-Joachim Schnittler 2 and Stefan-Martin Brand 1 1 Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany 2 Institute of Anatomy and Vascular Biology, University of Muenster, Muenster, Germany 3 Department of Physical Education and Sports History, University of Muenster, Muenster, Germany * These authors contributed equally to this work Correspondence to: Boris Schmitz, email: boris.schmitz@ukmuenster.de Keywords: miRNA; shear stress; performance; endothelium; high-intensity training (HIT) Received: November 17, 2018 Accepted: April 03, 2019 Published: June 04, 2019 ABSTRACT Circulatory microRNAs (c-miRNAs) are regulated in response to physical activity and may exert anti-atherosclerotic effects. Since the vascular endothelium is an abundant source of c-miRNAs, we aimed to identify novel vasculoprotective exercise-induced c-miRNAs by the combined analysis of published endothelial miRNA array data followed by in vivo and in vitro validation. We identified 8 different array-based publications reporting 185 endothelial shear stress-regulated miRNAs of which 13 were identified in ≥3 independent reports. Nine miRNAs had already been associated with physical activity. Of the remaining novel miRNAs, miR-98-3p and miR-125-5p were selected for further analysis due to reported vasculoprotective effects. Analysis in two different 4-week high-intensity interval training (HIIT) groups (group 1 [n=27]: 4x30 s, group 2 [n=25]: 8x15 s; all-out running) suggested significantly elevated miR-98 and miR-125a-5p levels in response to acute exercise at baseline and at follow-up. Endothelial in vitro shear stress experiments revealed increased miR-125a-5p and miR-98-3p levels in medium of human umbilical vein endothelial cells at 30 dyn/cm 2 after 20 and 60 min, respectively. Our results suggest that miR-98-3p and miR-125a-5p can be rapidly secreted by endothelial cells, which might be the source of increased c-miR-98-3p and -125a-5p levels in response to HIIT. Both miRNAs attenuate endothelial inflammation and may mediate vasculoprotective effects of physical exercise including HIIT.