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Volume 14 No. 05
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Scientific Investigations

Exosomal Cargo Properties, Endothelial Function and Treatment of Obesity Hypoventilation Syndrome: A Proof of Concept Study

Rakesh Bhattacharjee, MD1; Abdelnaby Khalyfa, PhD2; Ahamed A. Khalyfa, BSc2; Babak Mokhlesi, MD, MS3; Leila Kheirandish-Gozal, MD, MSc2; Isaac Almendros, PhD4; Eduard Peris, MSc2; Atul Malhotra, MD5; David Gozal, MD, MBA2
1Division of Respiratory Medicine, Department of Pediatrics, Rady Children's Hospital, The University of California San Diego, San Diego, California; 2Section of Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division University of Chicago, Chicago, Illinois; 3Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois; 4Universitat of Barcelona/IDIBAPS-CIBERES, Barcelona, Spain; 5Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California San Diego, San Diego, California

Study Objectives:

Longitudinal studies support the usage of positive airway pressure (PAP) therapy in treating obstructive sleep apnea (OSA) to improve cardiovascular disease. However, the anticipated benefit is not ubiquitous. In this study, we elucidate whether PAP therapy leads to immediate improvements on endothelial function, a subclinical marker of cardiovascular status, by examining the effect of circulating exosomes, isolated from patients before and after PAP therapy, on naive endothelial cells.

Methods:

We isolated plasma-derived circulating exosomes from 12 patients with severe OSA and obesity hypoventilation syndrome (OHS) before and after 6 weeks of PAP therapy, and examined their effect on cultured endothelial cells using several in vitro reporter assays.

Results:

We found that circulating exosomes contributed to the induction and propagation of OSA/OHS-related endothelial dysfunction (ie, increased permeability and disruption of tight junctions along with increased adhesion molecule expression, and reduced endothelial nitric oxide synthase expression), and promoted increased monocyte adherence. Further, when comparing exosomes isolated before and after PAP therapy, the disturbances in endothelial cell function were attenuated with treatment, including an overall cumulative decrease in endothelial permeability in all 12 subjects by 10.8% (P = .035), as well as detection of a subset of 4 differentially expressed exosomal miRNAs, even in the absence of parallel changes in systemic blood pressure or metabolic function.

Conclusions:

Circulating exosomes facilitate important intercellular signals that modify endothelial phenotype, and thus emerge as potential fundamental contributors in the context of OSA/OHS-related endothelial dysfunction. Exosomes may not only provide candidate biomarkers, but are also a likely and plausible mechanism toward OSA/OHS-induced cardiovascular disease.

Clinical Trial Registration:

Registry: ClinicalTrials.gov, Title: AVAPS-AE Efficacy Study, URL: https://clinicaltrials.gov/ct2/show/NCT01368614, Identifier: NCT01368614

Citation:

Bhattacharjee R, Khalyfa A, Khalyfa AA, Mokhlesi B, Kheirandish-Gozal L, Almendros I, Peris E, Malhotra A, Gozal D. Exosomal cargo properties, endothelial function and treatment of obesity hypoventilation syndrome: a proof of concept study. J Clin Sleep Med. 2018;14(5):797–807.


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