Deficiency of NOX1/NADPH Oxidase Leads to Pulmonary Vascular Remodeling
Objective—Involvement of reactive oxygen species derived from NADPH oxidase has been documented in the development of hypoxia-induced model of pulmonary arterial hypertension (PAH). Because the PAH-like phenotype was demonstrated in mice deficient in Nox1 gene (Nox1−/Y) raised under normoxia, the aim of this study was to clarify how the lack of NOX1/NADPH oxidase could lead to pulmonary pathology.
Approach and Results—Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1−/Y 9 to 18 weeks old. Because an increased number of α-smooth muscle actin-positive vessels were observed in Nox1−/Y, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1−/Y PASMCs, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1α and HIF-2α, factors were implicated in the pathogenesis of PAH. A significant decrease in a voltage-dependent K+ channel, Kv1.5 protein, and an increase in intracellular potassium levels were demonstrated in Nox1−/Y PASMCs. When a rescue study was performed in Nox1−/Y crossed with transgenic mice overexpressing rat Nox1 gene, impaired apoptosis and the level of Kv1.5 protein in PASMCs were almost completely recovered in Nox1−/Y harboring the Nox1 transgene.
Conclusions—These findings suggest a critical role for NOX1 in cellular apoptosis by regulating Kv1.5 and intracellular potassium levels. Because dysfunction of Kv1.5 is among the features demonstrated in PAH, inactivation of NOX1/NADPH oxidase may be a causative factor for pulmonary vascular remodeling associated with PAH.
- Received June 27, 2013.
- Accepted October 28, 2013.
- © 2013 American Heart Association, Inc.