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Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):110-9. doi: 10.1161/ATVBAHA.113.302107. Epub 2013 Nov 14.

Deficiency of NOX1/nicotinamide adenine dinucleotide phosphate, reduced form oxidase leads to pulmonary vascular remodeling.

Author information

1
From the Departments of Pharmacology (K. Iwata, K. Ikami, K.M., M.I., M.M., W.C., J.Z., K.Z., C.Y.-N.), Anatomy and Developmental Biology (D.S., T. Yokoyama), and Radioisotope Center (M.K.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan (T. Yamashita, O.O.); Department of Biomedical Engineering, Sapporo Medical University School of Medicine, Sapporo, Japan (N.T., Y.K.).

Abstract

OBJECTIVE:

Involvement of reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate, reduced form (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 terminal deoxynucleotidyl transferase dUTP nick end labeling 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 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.

KEYWORDS:

NADPH oxidase; apoptosis; potassium channel; pulmonary arterial hypertension

PMID:
24233492
DOI:
10.1161/ATVBAHA.113.302107
[Indexed for MEDLINE]

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