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/cm2 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.
Highlights
MicroRNAs have been identified as pivotal modulators of the systemic response to physical exercise and subsequent training adaptations [1,2,3,4]
Our results suggest that miR98-3p 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 high-intensity interval training (HIIT)
These c-miRNAs are preserved by association with RNA-binding proteins or small membranous vesicles and commonly involved in inter-cell communication with active regulation of target cell gene expression [13, 14]. c-miRNA production and secretion is responsive to different stimuli induced by physical exercise including shear stress and hypoxia [15,16,17]
Summary
MicroRNAs (miRNAs) have been identified as pivotal modulators of the systemic response to physical exercise and subsequent training adaptations [1,2,3,4]. The myocardium and vascular endothelium are an abundant source for miRNAs www.oncotarget.com that are selectively secreted into the blood stream where they can be detected as circulating miRNAs (c-miRNAs) [12] These c-miRNAs are preserved by association with RNA-binding proteins or small membranous vesicles and commonly involved in inter-cell communication with active regulation of target cell gene expression [13, 14]. While in vitro and ex vivo shear stress experiments have linked an increase in mean shear stress (i.e. constant laminar shear stress) to local antiatherosclerotic changes, it has been noted that beneficial effects of exercise on vascular function occur in arteries that are not subjected to a direct increase in shear stress [18, 23] To this end, selectively released miRNAs preserved by association with small membranous vesicles or RNAbinding proteins may be involved [13, 14]. In vitro shear stress experiments have been shown to alter the quantity of exosomes and the protein and/ or (mi)RNA content of exosomes derived from endothelial cells [33, 34]
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