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The Role of NADPH Oxidase in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension in Mice

¹ Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to C. Michael Hart, M.D., Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Atlanta VAMC (151-P), 1670 Clairmont Rd., Decatur, GA 30033. E-mail: Michael.hart3{at}va.gov

Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O₂^–·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase–derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O₂ 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase–derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

Key Words: hypoxia • pulmonary hypertension • nitric oxide • NADPH oxidase

CLINICAL RELEVANCE Chronic intermittent hypoxia (CIH)-induced alterations in NADPH oxidase–derived reactive oxygen species (ROS) contribute to the development of pulmonary hypertension and vascular remodeling. NADPH oxidase–derived ROS represent potential novel targets for intervention in OSA-associated vascular derangements.

 

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