Vascular Endothelial-Cadherin Cleavage in Sleep Apnea Patients: New Insights for Intermittent Hypoxia-Related Endothelial Permeability

Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH). IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n=6) or a simulated IH (SIH) (n=6) for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF-α), inducible NO synthase (iNOS), vascular endothelial growth factor (VEGF), and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.

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Roles and Mechanisms of Obstructive Sleep Apnea-Hypopnea Syndrome and Chronic Intermittent Hypoxia in Atherosclerosis: Evidence and Prospective

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/8215082 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Linqin Ma ◽

Jingchun Zhang ◽

Yue Liu

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Intermittent Hypoxia ◽

Underlying Mechanism ◽

Endothelial Injury ◽

Current Evidence ◽

Chronic Intermittent Hypoxia ◽

Vascular Endothelial ◽

Obstructive Sleep ◽

Hypopnea Syndrome

The morbidity and mortality of obstructive sleep apnea-hypopnea syndrome (OSAHS) are regarded as consequences of its adverse effects on the cardiovascular system. Chronic intermittent hypoxia (CIH) induced by OSAHS can result in vascular endothelial injury, thus promoting development of atherosclerosis (AS). Studies have shown that CIH is an independent risk factor for the occurrence and development of AS, but the underlying mechanism remains unclear. Here, we review clinical and fundamental studies reported during the last 10 years on the occurrence and development of AS mediated by CIH, focusing on inflammation, oxidative stress, insulin resistance, cell apoptosis, vascular endothelial injury, platelet activation, and neuroendocrine disorders. This review will offer current evidence and perspective to researchers for the development of effective intervention strategies for OSAHS-related cardiocerebrovascular diseases.

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Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00686.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. H2745-H2753 ◽

Cited By ~ 68

Author(s):

Larissa Eiselein ◽

Dennis W. Wilson ◽

Michael W. Lamé ◽

John C. Rutledge

Keyword(s):

Endothelial Cells ◽

Lipoprotein Lipase ◽

Endothelial Permeability ◽

Vascular Endothelial ◽

Aortic Endothelial Cells ◽

Zonula Occludens ◽

Vascular Endothelial Cadherin ◽

Zonula Occludens 1 ◽

Human Aortic Endothelial Cells ◽

Aortic Endothelial

Products generated from lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TGRL) are reported to increase endothelial layer permeability. We hypothesize that these increases in permeability result from the active rearrangement and dissolution of the junctional barrier in human aortic endothelial cells, as well as induction of the apoptotic cascade. Human aortic endothelial cells were treated with TGRL lipolysis products generated from coincubation of human TGRL plus lipoprotein lipase. Measurement of transendothelial electrical resistance demonstrated a time-dependent decrease in endothelial barrier function in response to TGRL lipolysis products. Immunofluorescent localization of zonula occludens-1 (ZO-1) showed radial rearrangement along cell borders after 1.5 h of treatment with lipolysis products. A concurrent redistribution of F-actin from the cell body to the cell margins was observed via rhodamine phalloidin staining. Immunofluorescent imaging for occludin and vascular endothelial cadherin showed that these proteins relocalize as well, although these changes are less prominent than for ZO-1. Western analysis of cells exposed to lipolysis products for 3 h revealed the fragmentation of ZO-1, a reduction in occludin, and no change of vascular endothelial cadherin. Lipolysis products also increased caspase-3 activity and induced nuclear fragmentation. Treatments did not cause oncosis in cells at any point during the incubation. These results demonstrate that TGRL lipolysis products play an important role in the regulation of endothelial permeability, the organization of the actin cytoskeleton, the localization and expression of junctional proteins, especially ZO-1, and the induction of apoptosis.

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