title: Effect on Intermittent Hypoxia on Plasma Exosomal Micro RNA Signature and Endothelial Function in Healthy Adults.
abstract: Intermittent hypoxia (IH) is associated with increased risk of cardiovascular disease. Exosomes are secreted by most cell types and released in biological fluids, including plasma, and play a role in modifying the functional phenotype of target cells. Using an experimental human model of IH, we investigated potential exosome-derived biomarkers of IH-induced vascular dysfunction.
  
  
  
  Ten male volunteers were exposed to room air (D0), IH (6 h/day) for 4 days (D4) and allowed to recover for 4 days (D8). Circulating plasma exosomes were isolated and incubated with human endothelial monolayer cultures for impedance measurements and RNA extracted and processed with messenger RNA (mRNA) arrays to identify gene targets. In addition, immunofluorescent assessments of endothelial nitric oxide synthase (eNOS) mRNA expression, ICAM-1 cellular distribution were conducted.
  
  
  
  Plasma exosomal micro RNAs (miRNAs) were profiled. D4 exosomes, primarily from endothelial sources, disrupted impedance levels compared to D0 and D8. ICAM-1 expression was markedly upregulated in endothelial cells exposed to D4 exosomes along with significant reductions ineNOSexpression. Microarray approaches identified a restricted and further validated signature of exosomal miRNAs in D4 exosomes, and mRNA arrays revealed putative endothelial gene target pathways.
  
  
  
  In humans, intermittent hypoxia alters exosome cargo in the circulation which promotes increased permeability and dysfunction of endothelial cellsin vitro. A select number of circulating exosomal miRNAs may play important roles in the cardiovascular dysfunction associated with OSA by targeting specific effector pathways.
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Science Division, University of Chicago, Chicago, IL.
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, IL.
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Science Division, University of Chicago, Chicago, IL.
authors.forename: Ahamed A
authors.initials: AA
authors.lastname: Khalyfa
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Foster
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Beaudin
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, IL.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hanly
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada.|Faculty of Kinesiology, University of Calgary, Calgary Alberta, Canada.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Poulin
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Science Division, University of Chicago, Chicago, IL.
authors.forename: David
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000235:genetics / Q000503:physiopathology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D055354:Exosomes / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D020181:Sleep Apnea, Obstructive / Q000235:genetics* / Q000503:physiopathology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: cardiovascular disease; circulating miRNAs; endothelium; exosomes; experimental human model; healthy human volunteers; intermittent hypoxia; sleep apnea