Chronic intermittent hypoxia causes endothelial dysfunction in a mouse model of diet-induced obesity.
BACKGROUND
Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity.


METHODS
Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR.


RESULTS
Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (Emax: HFIH 78±2%, p<0.0001) when compared to the other groups (Emax: HFIA 95±0.7%, CDIH 94±2%, CDIA 97±1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (Emax: HFIH: 179±10% vs. HFIA: 149±11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68±0.04 vs. 0.41±0.03 μM, p<0.05) but were greatest in the HFIH group (0.83±0.08 μM, p<0.05). However, there was no significant increase in MDA levels in the HFIA group (0.45±0.03 μM, p=NS) when compared to all other groups. Similar effects were observed with CRP levels; CRP levels were significantly higher in the CDIH group compared with intermittent air (10.39±0.38 vs. 8.70±0.21 μg/ml, p<0.05) but the HFIH had the greatest levels of CRP (11.87±0.31 μg/ml, p<0.05). In the HFIA group, CRP levels were not elevated (9.96±0.37 μg/ml, p=NS). Nevertheless, total antioxidant capacity and eNOS gene expression were not significantly different in the groups.


CONCLUSIONS
CIH caused endothelial dysfunction in mice fed an obesogenic diet. Inflammation and oxidative stress were increased in CIH and an obesogenic diet exacerbated these effects.
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Mohammad
M
Badran
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Saeid
S
Golbidi
Department of Pediatrics, University of British Columbia, Child & Family Research Institute, Vancouver, Canada.
Angela
A
Devlin
Division of Critical Care, Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Sleep Disorders Program, UBC Hospital, Vancouver, BC, Canada; Division of Critical Care Medicine, Providence Healthcare, Vancouver, BC, Canada.
Najib
N
Ayas
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. Electronic address: ilaher@interchange.ubc.ca.
Ismail
I
Laher
D000818:Animals; D001011:Aorta / Q000201:enzymology; D002097:C-Reactive Protein / Q000032:analysis; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications* / Q000209:etiology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009213:Myography; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D020181:Sleep Apnea, Obstructive / Q000150:complications; D014664:Vasodilation / Q000502:physiology
D008315:Malondialdehyde; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III
Inflammation; Intermittent hypoxia; Obesity; Oxidative stress; Sleep apnea; Vascular endothelium