NOX2 inhibition attenuates oxidative stress and eNOS uncoupling in pulmonary arteries of rats following simulated air diving

Qingbo Gong, Lin Xiao and Song Wang

PLOS ONE, 2026, vol. 21, issue 7, 1-14

Abstract: Simulated diving and decompression can impair endothelial function, but the upstream oxidant sources and their relationship with endothelial nitric oxide synthase (eNOS) coupling in the pulmonary circulation remain unclear. We investigated whether NADPH oxidase 2 (NOX2) is associated with oxidative stress, tetrahydrobiopterin (BH4) depletion, altered eNOS coupling, and pulmonary endothelial dysfunction after simulated air diving. Eighteen male Sprague–Dawley rats were assigned to three groups: control, decompression stress, and decompression stress with the NOX2 inhibitor GSK2795039 (100 mg/kg, intraperitoneal) administered before pressurization. Decompression stress was induced by hyperbaric exposure to 600 kPa for 1 h followed by decompression to ambient pressure; pulmonary arteries were collected 1 h after decompression. We evaluated NOX2 expression, oxidative stress indices, BH4 content, eNOS phosphorylation and dimer/monomer ratio, nitric oxide metabolites (nitrate plus nitrite), markers associated with endothelial activation, and vasoreactivity. Compared with controls, decompression stress increased NOX2 expression, reactive oxygen species and lipid peroxidation, decreased superoxide dismutase activity, reduced BH4 and nitric oxide metabolites. It also caused a shift in eNOS towards a lower dimer/monomer ratio, increased endothelin-1 and adhesion molecules, and impaired endothelium-dependent relaxation, though endothelium-independent relaxation remained intact. GSK2795039 pretreatment attenuated oxidative stress, improved BH4 availability, restored nitric oxide metabolites, and decreased markers of endothelial activation, partially improving endothelium-dependent relaxation. These findings suggest that NOX2-associated oxidative stress contributes to reduced BH4 availability and eNOS coupling imbalance, leading to pulmonary endothelial dysfunction after decompression.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0351145

DOI: 10.1371/journal.pone.0351145

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