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1 Departments of Medicine and Cell Biology, Duke University Medical Center, Durham, NC, USA
2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: johnqliu{at}hotmail.com.
Chronic exposure to low O2 tension induces pulmonary arterial hypertension (PAH), which is characterized by vascular remodeling and enhanced vasoreactivity. Recent evidence suggests that reactive oxygen species (ROS) may be involved in both processes. In this study, we critically examine the role superoxide and NADPH oxidase plays in the development of chronic hypoxic PAH. Chronic hypoxia (CH) (10% O2 for 3 weeks) caused a significant increase in superoxide production in intrapulmonary arteries (IPA) of wild type (wt) mice as measured by lucigenin- enhanced chemiluminescence. CH-induced increase in the generation of ROS was obliterated in NADPH oxidase (gp91phox) KO mice, suggesting that NADPH oxidase was the major source of ROS. Importantly, pathological changes associated with CH-induced PAH (mean right ventricular pressure, medial wall thickening of small PAs, and right heart hypertrophy), were completely abolished in NADPH oxidase (gp91phox) KO mice. CH potentiated vasoconstrictor responses of isolated IPAs to both 5-hydroxytryptamine (5-HT) and the thromboxane mimetic, U46619. Administration of CuZn superoxide dismutase to isolated IPA significantly reduced CH-enhanced superoxide levels and reduced the CH-enhanced vasoconstriction to 5-HT and U46619. Additionally, CH-enhanced superoxide production and vasoconstrictor activity seen in wt IPA were markedly reduced in IPA isolated from NADPH oxidase (gp91phox) KO mice. These results demonstrate a pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH.
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