Endothelial-derived cardiovascular disease-related microRNAs elevated with prolonged sitting pattern among postmenopausal women

Ya-Ju Chang,Dorothy D Sears,Suneeta Godbole,Brinda Rana,Fatima Tuz-Zahra,Marta M Jankowska,Matthew A Allison,Cheryl L Rock,Yesenia Avitia,John Bellettiere,David W Dunstan,Loki Natarajan

doi:10.1038/s41598-021-90154-1

Abstract

Time spent sitting is positively correlated with endothelial dysfunction and cardiovascular disease risk. The underlying molecular mechanisms are unknown. MicroRNAs contained in extracellular vesicles (EVs) reflect cell/tissue status and mediate intercellular communication. We explored the association between sitting patterns and microRNAs isolated from endothelial cell (EC)-derived EVs. Using extant actigraphy based sitting behavior data on a cohort of 518 postmenopausal overweight/obese women, we grouped the woman as Interrupted Sitters (IS; N = 18) or Super Sitters (SS; N = 53) if they were in the shortest or longest sitting pattern quartile, respectively. The cargo microRNA in EC-EVs from the IS and SS women were compared. MicroRNA data were weighted by age, physical functioning, MVPA, device wear days, device wear time, waist circumference, and body mass index. Screening of CVD-related microRNAs demonstrated that miR-199a-5p, let-7d-5p, miR-140-5p, miR-142-3p, miR-133b level were significantly elevated in SS compared to IS groups. Group differences in let-7d-5p, miR-133b, and miR-142-3p were validated in expanded groups. Pathway enrichment analyses show that mucin-type O-glycan biosynthesis and cardiomyocyte adrenergic signaling (P < 0.001) are downstream of the three validated microRNAs. This proof-of-concept study supports the possibility that CVD-related microRNAs in EC-EVs may be molecular transducers of sitting pattern-associated CVD risk in overweight postmenopausal women.

Highlights

Time spent sitting is positively correlated with endothelial dysfunction and cardiovascular disease risk
In preparation for analysis of the clinical samples, we examined the specificity of CD144 for endothelial cell (EC)-extracellular vesicles (EVs) and the biochemical and ultrastructural characteristics of the CD144 + EC-derived EVs (EC-EVs)
Proof of concept study, sitting patterns consisting of longer mean bout duration (SS + ; 62.8 ± 23.4 min) were associated with significant elevation of let-7d-5p, miR-133b, and miR-142-3p in circulating EC-EVs, compared to patterns with more interrupted, shorter sitting bouts (IS + ; 25.9 ± 2.8 min) among 85 overweight/obese postmenopausal women

Summary

Introduction

Time spent sitting is positively correlated with endothelial dysfunction and cardiovascular disease risk. Using device-based measures of sitting behavior, we recently showed that longer total sitting time and mean sitting bout duration (i.e., sitting pattern) were associated with cardiometabolic and cancer risk biomarkers among 518 overweight and obese postmenopausal w omen[7] In this population, the women had a mean (SD) daily sitting time of 9.1 (1.6) hours and a mean (SD) sitting bout duration of 39.2 (15.5) minutes. The association between prolonged sitting and endothelial dysfunction are becoming clearer, the molecular mechanisms that link physiological alterations and pathological progression remain unknown In this regard, microRNAs (miRs) in endothelial cells (ECs) are one of the molecule classes that changes with cellular status in response to aging, oxidized low-density lipoprotein, hyperglycemia, hypertension, and magnitudes of antegrade blood flow[14,15]. Twelve miRs isolated from human plasma EVs have been identified to potentially impact muscle remodeling and growth resulting from acute e xercise[20]

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