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

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 exerciseinduced 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.

Changes in circulating microRNA and arterial stiffness following high‐intensity interval and moderate intensity continuous exercise

“…High intensity interval exercise elicits greater shear rate along the vessel wall as compared with a matched bout of moderate continuous exercise (Atkinson, Carter, et al, 2015; Johnson & Wallace, 2012; McManus, Sletten, & Green, 2019). The pattern and magnitude of shear stress is important in regulating endothelial cell expression of miRs (Donaldson et al., 2018; Lee & Chiu, 2019) and it was recently shown that increased shear stress elicits the release of miR from cultured endothelial cells that are also increased in circulation in response to acute exercise ( Schmitz et al., 2019). Other factors that could contribute to changes in arterial stiffness include acute elevations in inflammation and ROS, stimuli known to increase with exercise in an intensity‐dependent manner (Allen, Sun, & Woods, 2015; Johnson et al., 2012; McClean et al., 2015; Vlachopoulos et al., 2005; Vucinovic et al., 2015).…”

“…The levels of specific ci‐miRs correlate with arterial stiffness in humans (Deng et al., 2017; Parthenakis et al., 2017; Van Craenenbroeck et al., 2016). Additionally, in vitro and animal experiments have shown that changes in specific vascular stimuli such as shear stress and inflammation affect the expression and release of microRNAs from vascular cells, suggesting these molecules may play roles in exercise intensity‐dependent changes in arterial stiffness (Alexy, Rooney, Weber, Gray, & Searles, 2014; Donaldson et al., 2018; Hale et al., 1843; Lee & Chiu, 2019; Schmitz et al., 2019; Zhou et al., 2013).…”

Sex Differences in High-Intensity Interval Training–Are HIIT Protocols Interchangeable Between Females and Males?

“…The two HIIT protocols were matched for total workload and duration (Table 1; Schmitz et al, 2019c). Respective metabolic equivalents (METs) were estimated according to the Compendium of Physical Activities (Ainsworth et al, 2000) with 8.0 METs for running at 8 km h −1 (code 12030, for active recovery) and 19.0 METs for running at all-out speed (code 12132) as reported previously .…”

The Molecular Signature of High-intensity Training in the Human Body

“…Besides other molecular factors, miRNAs and microparticles have the potential to spread molecular signalling throughout the body via the vascular system. miRNAs (such as microRNAs -16, -21, and -126) attenuate endothelial inflammation and may mediate vascular-protective effects of physical exercise including HIT [54,55].…”