Ed in animal models of OSA [4]. Theseabnormalities are linked to impaired

Ed in animal models of OSA [4]. Theseabnormalities are linked to impaired activity of endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide (NO), and whose bioavailability is required for normal function of the endothelium [5,6]. In the last few years, increased systemic levels of several inflammatory markers, including TNF-a, IL-6, IL-8 and ICAM-1, have been associated with OSA, suggesting that inflammation plays an important role in the pathophysiology of OSA, and possibly its vascular complications [7,8,9,10,11]. However, the role of HIF-1a, a 10457188 transcription factor essential for oxygen homeostasis that is activated in response to hypoxia remains controversial in OSA studies [11,12,13]. Intermittent hypoxia-induced increase in HIF-1a protein levels has been suggested as an adaptive 16574785 responseBiomarkers of Vascular Dysfunction in Sleep Apneato OSA [12,14,15]; however, negative effects of HIF-1a activation, such as hypertension and ischemic injury, have also been reported in animal models of OSA [16]. Although OSA is a fairly well investigated disease, the mechanistic insights into its effects on the vasculature, and specifically EC dysfunction, remain to be elucidated. Given the heavy health burden that the cardiovascular risk of OSA represents, reliable biomarkers that could estimate this risk and help define preventive and therapeutic measures are clearly needed [17]. Clinical data suggest variable cardiovascular risk in OSA populations, and indicate that both protective and deleterious pathways may be affected in OSA. Accordingly, defining the mechanisms underlying differential patient susceptibility to OSA consequences is desirable. In this study, we analyzed expression levels of select genes, chosen based on their involvement in the inflammatory/adaptive response of the 11089-65-9 web vasculature to hypoxia, in skin biopsies of patients with OSA. Our aim was to identify a “gene signature” panel in the skin of OSA patients that could serve as a diagnostic and prognostic biomarker of disease severity, and ultimately to predict possible cardiovascular risk in the future, after validation in long-term clinical studies. In addition, we aimed to validate this gene signature in experimental models of OSA, using mice and in vitro cell cultures exposed to IH. We hypothesized that the pattern of gene regulation in mouse aorta and EC exposed to IH is also exhibited in the skin vasculature of OSA patients.and healthy controls (AHI,10/h) (Table 1). Title Loaded From File Subjects with major cardiac, respiratory, metabolic or sleep disorders other than OSA were excluded. There were no significant differences in BMI between OSA groups; however, the control group was somewhat younger than both OSA groups. All polysomnography (PSG) variables were within the normal range for the control group, with increasing AHI for the OSA groups with mild and severe hypoxemia. The study was approved by the Partners’ Human Research Committee, and all subjects gave written informed consent. While some subjects participated in prior research [18], none of the findings of the present study has been previously published.Study designThis was a cross-sectional study that consisted of a screening visit to ensure eligibility, and standard in-laboratory diagnostic polysomnography (PSG) conducted between 10 PM and 6 AM, followed by microcirculatory reactivity testing and a skin biopsy obtained after PSG completion. Subjects were asked to adhere to a low-nitrate diet for 72 h prior to a.Ed in animal models of OSA [4]. Theseabnormalities are linked to impaired activity of endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide (NO), and whose bioavailability is required for normal function of the endothelium [5,6]. In the last few years, increased systemic levels of several inflammatory markers, including TNF-a, IL-6, IL-8 and ICAM-1, have been associated with OSA, suggesting that inflammation plays an important role in the pathophysiology of OSA, and possibly its vascular complications [7,8,9,10,11]. However, the role of HIF-1a, a 10457188 transcription factor essential for oxygen homeostasis that is activated in response to hypoxia remains controversial in OSA studies [11,12,13]. Intermittent hypoxia-induced increase in HIF-1a protein levels has been suggested as an adaptive 16574785 responseBiomarkers of Vascular Dysfunction in Sleep Apneato OSA [12,14,15]; however, negative effects of HIF-1a activation, such as hypertension and ischemic injury, have also been reported in animal models of OSA [16]. Although OSA is a fairly well investigated disease, the mechanistic insights into its effects on the vasculature, and specifically EC dysfunction, remain to be elucidated. Given the heavy health burden that the cardiovascular risk of OSA represents, reliable biomarkers that could estimate this risk and help define preventive and therapeutic measures are clearly needed [17]. Clinical data suggest variable cardiovascular risk in OSA populations, and indicate that both protective and deleterious pathways may be affected in OSA. Accordingly, defining the mechanisms underlying differential patient susceptibility to OSA consequences is desirable. In this study, we analyzed expression levels of select genes, chosen based on their involvement in the inflammatory/adaptive response of the vasculature to hypoxia, in skin biopsies of patients with OSA. Our aim was to identify a “gene signature” panel in the skin of OSA patients that could serve as a diagnostic and prognostic biomarker of disease severity, and ultimately to predict possible cardiovascular risk in the future, after validation in long-term clinical studies. In addition, we aimed to validate this gene signature in experimental models of OSA, using mice and in vitro cell cultures exposed to IH. We hypothesized that the pattern of gene regulation in mouse aorta and EC exposed to IH is also exhibited in the skin vasculature of OSA patients.and healthy controls (AHI,10/h) (Table 1). Subjects with major cardiac, respiratory, metabolic or sleep disorders other than OSA were excluded. There were no significant differences in BMI between OSA groups; however, the control group was somewhat younger than both OSA groups. All polysomnography (PSG) variables were within the normal range for the control group, with increasing AHI for the OSA groups with mild and severe hypoxemia. The study was approved by the Partners’ Human Research Committee, and all subjects gave written informed consent. While some subjects participated in prior research [18], none of the findings of the present study has been previously published.Study designThis was a cross-sectional study that consisted of a screening visit to ensure eligibility, and standard in-laboratory diagnostic polysomnography (PSG) conducted between 10 PM and 6 AM, followed by microcirculatory reactivity testing and a skin biopsy obtained after PSG completion. Subjects were asked to adhere to a low-nitrate diet for 72 h prior to a.