Molecular biomarkers of vascular dysfunction in obstructive sleep apnea.
Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.
Center for Vascular Biology Research, Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America. ekaczmar@bidmc.harvard.edu
Elzbieta
E
Kaczmarek
Jessie P
JP
Bakker
Douglas N
DN
Clarke
Eva
E
Csizmadia
Olivier
O
Kocher
Aristidis
A
Veves
Francesco
F
Tecilazich
Christopher P
CP
O'Donnell
Christiane
C
Ferran
Atul
A
Malhotra
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008833:Microcirculation; D008875:Middle Aged; D017286:Polysomnography; D020181:Sleep Apnea, Obstructive / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
D015415:Biomarkers