Abstract
Vascular dysfunction and insulin resistance (IR) are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). While it is recognized that the balance between vasoconstrictive (endothelin-1) and vasodilatory molecules (nitric oxide, NO) determine vascular profile, molecular mechanisms contributing to vascular dysfunction and IR in OSA are not completely understood. Caveolin-1 is a membrane protein which regulates endothelial nitric oxide synthase (eNOS) activity which is responsible for NO generation and cellular insulin-signaling. Hence, we examined the effects of IH on caveolin-1, eNOS, and endothelin-1 in human coronary artery endothelial cells in the context of IR. Chronic 3-day IH exposure up-regulated caveolin-1 and endothelin-1 expression while reducing NO. Also, IH altered insulin-mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription. Similarly, caveolin-1 overexpression attenuated basal and insulin-stimulated NO synthesis along with impaired insulin-dependent activation of AKT and eNOS, with no effect on insulin-stimulated ERK1/2 phosphorylation and endothelin-1 transcription. Our data suggest that IH contributes to a vasoconstrictive profile and to pathway-selective vascular IR, whereby insulin potentiates ET-1 expression. Moreover, IH may partly mediate its effects on NO and insulin-signaling via upregulating caveolin-1 expression.
Highlights
Obstructive sleep apnea (OSA) is a common sleep breathing disorder, and is an acknowledged risk factor for cardiovascular disease[1]
NO is generated by endothelial nitric oxide synthase activity, which is regulated by caveolin-1, by directly binding to and blocking the active site of eNOS6
In this study we demonstrate for the first time that intermittent hypoxia (IH) alters insulin-signaling and stimulates cav-1 expression which may together promote changes in human coronary artery endothelial cells (HCAEC) consistent with vasoconstriction
Summary
Obstructive sleep apnea (OSA) is a common sleep breathing disorder, and is an acknowledged risk factor for cardiovascular disease[1]. Endothelial dysfunction is characterized by decreased bioavailability of endothelium-derived nitric oxide (NO), and is highly prevalent in OSA2. Treatment with continuous positive airway pressure therapy improves vascular function, hypertension as well as insulin-sensitivity[1,4]. This suggests a role of chronic IH in eliciting endothelial dysfunction and IR. We tested the hypothesis that IH increases cav-1 and mediates vascular dysfunction and IR with consequent decreases in NO, increases in ET-1, and selectively impaired insulin signaling. N: normoxia (white bars); IH: intermittent hypoxia (black bars); eNOS: endothelial nitric oxide synthase. We hypothesized that IH dependent effects on vasoactive compounds and insulin cellular signaling may be mimicked by cav-1 overexpression
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