Obstructive sleep apnea (OSA), obesity, or the combination thereof, increase the risk of multisystem morbidity. Among the several important morbid consequences, cardiovascular disease (CVD) risk was identified, and exhibited disease severity related prevalence changes as illustrated by carotid intima-media thickness (cIMT) or endothelial dysfunction (ED). However, at any level of OSA, there will be patients with CVD risk and those without. Most recently, we have identified that patients with OSA exhibit unique miRNA signatures in their plasma, and hypothesized that OSA will lead to release of exosomes to the systemic circulation whose unique miRNA signatures mechanistically underlie the presence of CVD risk. To confirm such hypotheses we propose: To determine whether plasma-derived exosomes in adults with and without OSA and with low CVD risk differ from age-, gender-, BMI-, and ethnicity-matched adults with and without OSA but with high CVD risk in their cell source of exosomes, in vitro disruption properties of the endothelial cell barrier, and changes in eNOS (endothelial nitric oxide synthase) expression , effect of exosomes on monocyte adhesion to endothelium and changes in endothelial cell ICAM1 expression, effect of exosomes on in vitro angiogenesis and wound healing, and in vivo alterations in endothelial function in a murine model (SA#1). We will also determine whether CPAP treatment or no treatment of adults with OSA lead to changes in plasma exosomal biological properties that reflect temporal changes in CVD risk by taking advantage of de-identified plasma samples from the EPIOSA Study in Spain (SA#2). Lastly, we will identify plasma exosomal miRNA cargo signatures in OSA-CVDhigh and OSA-CVDlow and explore whether use of mimic miRNAs or siRNAs of the differentially expressed exosomal miRNAs can reverse or accentuate (a) in vitro disruption properties of the endothelial cell barrier, and changes in eNOS expression; (b) effect of exosomes on monocyte adhesion to endothelium and changes in endothelial cell expression of ICAM1; (c) effect of exosomes on in vitro angiogenesis; (d) in vivo alterations in endothelial function in a murine model. Thus, the proposed studies will not only identify the unique potential biomarker value of miRNAs in the exosomal cargo along with identification of their putative gene targets and biological roles in CVD risk, but will also enable improved understanding of the mechanisms underlying the accelerated atherosclerosis associated with OSA, and potentially permit development of miRNA targeted therapeutic approaches to prevent the important long-term complications of this highly prevalent disorder.
Sleep apnea patients are at increased risk of developing cardiovascular morbidity, as illustrated by increased intima-media thickness and endothelial dysfunction, both of which are predictors of hardening of the arteries and heart disease. However, we still do not understand why at any level of sleep apnea severity, some patients have increased cardiovascular disease risk and others do not. We now propose that small structures called exosomes in the circulating blood that contain genetic material such as microRNAs, and that such genetic material can damage blood vessels leading to blood vessel dysfunction and possibly leading to new therapies for patients.
