TY - JOUR
T1 - Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1
AU - Hoffmann, Michal S.
AU - Singh, Prachi
AU - Wolk, Robert
AU - Narkiewicz, Krzysztof
AU - Somers, Virend K.
N1 - Funding Information:
Funding from the following sources is acknowledged. MSH is supported by PNRF-213-AI-1/07 grant. PS is supported by AHA Scientist Development grant 11SGD7260046 and NIH R01 HL65176 , KN is supported by PNRF-213-AI-1/07 grant, and VKS is supported by NIH R01 HL65176 as well as UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS) . The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
PY - 2013/12
Y1 - 2013/12
N2 - Objective: Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. Methods: In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. Results: Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. Conclusion: Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA.
AB - Objective: Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. Methods: In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. Results: Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. Conclusion: Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA.
KW - Dual specificity phosphatase 1
KW - Intermittent hypoxia
KW - Obstructive sleep apnea
KW - Reactive oxygen species
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U2 - 10.1016/j.atherosclerosis.2013.09.033
DO - 10.1016/j.atherosclerosis.2013.09.033
M3 - Article
C2 - 24267255
AN - SCOPUS:84888094948
SN - 0021-9150
VL - 231
SP - 378
EP - 383
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -