title: Intermittent hypoxia induces NF-κB-dependent endothelial activation via adipocyte-derived mediators.
abstract: Aberrant release of adipocytokines from adipose tissues dysregulates cardiometabolic functions. The present study hypothesizes that chronic intermittent hypoxia (IH) present in obstructive sleep apnea leads to adipose tissue dysfunction, which in turn contributes to vascular pathogenesis. The effect of IH was evaluated in adipose depots and aortic tissues in lean rats in vivo. Furthermore, the cellular and molecular mechanisms underlying pathophysiological interactions between adipocytes and endothelial cells were investigated in vitro. The in vivo results showed that IH induced upregulation of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in subcutaneous and periaortic adipose tissues and downregulated phosphorylation of endothelial nitric oxide synthase [eNOS (ser1177)] in the aorta with activation of Erk and p38 MAPK. In support, cultured adipocytes demonstrated IH-induced elevations of NADPH oxidase 4, phosphorylation of Erk, NF-κBp65, and inducible NOS (iNOS) and increased expression of IL-6 and MCP-1. Likewise, endothelial EA.hy926 (EA) cells exposed to IH showed eNOS (ser1177) and intracellular cGMP reduction, whereas MCP-1 and iNOS expression were upregulated. Treatment of EA cells with conditioned media derived from IH-exposed cultured adipocytes caused nuclear translocation of NF-κBp65 and elevation of MCP-1, which were prevented by addition of neutralizing IL-6 antibodies to the conditioned media. Recombinant IL-6 in addition to IH induced further MCP-1 release and iNOS protein expression in EA cells, which were prevented by pharmacological inhibition of Erk, p38, and NF-κB. These findings suggest that IH could induce adipose tissue inflammation, which may cross talk with endothelial cells via adipocyte-derived mediators such as IL-6, and promote NF-κB-dependent endothelial dysfunction.
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Mary Y K
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong;
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Judith C W
authors.initials: JC
authors.lastname: Mak
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong msmip@hku.hk.
authors.forename: Mary S M
authors.initials: MS
authors.lastname: Ip
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: NF-κB; adipose inflammation; endothelial function; intermittent hypoxia