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Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2

Schulz, Richarda; Murzabekova, Gulsinaa; Egemnazarov, Bakytbeka; Kraut, Simonea; Eisele, Hans-Joachima; Dumitrascu, Rioa; Heitmann, Jörga; Seimetz, Michaela; Witzenrath, Martinb; Ghofrani, Hossein A.a; Schermuly, Ralph T.a; Grimminger, Friedricha; Seeger, Wernera,c; Weissmann, Norberta

doi: 10.1097/HJH.0000000000000016
ORIGINAL PAPERS: Pathophysiological aspects

Objectives: To investigate whether NADPH oxidase 2 (NOX2), a major source of reactive oxygen species (ROS), contributes to the emergence of arterial hypertension in a murine model of sleep apnea.

Background: Obstructive sleep apnea (OSA) is a risk factor for arterial hypertension and it is linked to oxidative stress.

Methods: C57BL/6J mice were exposed to chronic intermittent hypoxia (CIH) for 6 weeks (5 days/week, 8 h/day, alternating cycles of hypoxia and normoxia, each lasting 120 s, nadir FiO2: 7%). Blood pressure was monitored by telemetric catheters implanted into the abdominal aorta. Pharmacological inhibition of NOX by apocynin and NOX2-deficient mice were used to assess the role of NOX in CIH-induced arterial hypertension. NOX2 gene expression was measured by real-time PCR in different cardiovascular tissues.

Results: When compared with room air conditions, wild-type mice showed significant blood pressure elevations after exposure to CIH. This response was attenuated after treating animals with apocynin and in NOX2 (=gp91phox) knockout mice, whereas NOX2 was not upregulated in the heart, aorta, and femoral/carotid arteries of CIH mice.

Conclusion: We suggest that the CIH-induced arterial hypertension is mediated by ROS derived from an activation of NOX2 within cells located outside the cardiovascular system.

aUniversities of Giessen and Marburg Lung Center, Excellence Cluster Cardio-Pulmonary System, German Lung Research Center, Justus-Liebig-University Giessen, Giessen

bDepartment of Internal Medicine, Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin

cDepartment of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

Correspondence to Richard Schulz, MD, Department of Sleep Medicine, Universities of Giessen and Marburg Lung Center, Klinikstr. 33, 35392 Giessen, Germany. Tel: +49 641 985 57030; fax: +49 641 985 42599; e-mail:

Abbreviations: BP, blood pressure; CIH, chronic intermittent hypoxia; eNOS, endothelial nitric oxide synthase; NOX, NADPH oxidase; OSA, obstructive sleep apnea; ROS, reactive oxygen species

Received 11 December, 2012

Accepted 4 September, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins