Ablation of glutaredoxin 1 promotes pulmonary angiogenesis and alveolar formation in hyperoxia-injured lungs by modifying HIF-1α stability and inhibiting the NF-κB pathway

Abstract

Glutaredoxin 1 (Grx1) is an important thiol transferase that catalyses the deglutathionylation of proteins through its active site. Deletion of Grx1 increases levels of glutathione-protein adducts and improves ischaemic revascularization. In this study, we investigated whether the absence of Grx1 ameliorates pathological changes in blood vessels and alveoli in a mouse model exposed to hyperoxic conditions. High oxygen exposure for three consecutive weeks increased the levels of Grx1 in the lungs of hyperoxic mice from control levels, while Grx1 levels in Grx1 knockout (KO) mice were significantly reduced under high oxygen conditions. Exposure to 85% oxygen for 21 days reduced alveolarization in wild-type (WT) mice but increased the numbers of alveoli and the survival rate of Grx1 KO littermates. Importantly, vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor A (VEGFA) expressions were increased in Grx1 KO mice after hyperoxia treatment, and these effects were probably attributable to increased hypoxia-inducible factor (HIF)-1α expression. On the other hand, in response to nuclear factor (NF)-κB inhibition by Grx1 ablation, chemokine and caspase-3 levels were reduced, although the Bcl-2:Bax ratio was increased. Here, we provide evidence that Grx1 plays an important role in regulating pathological damage under hyperoxic conditions by promoting HIF-1α stability and inhibiting the NF-κB pathway in vivo. Our study highlights the functional importance of the Grx1/protein S-glutathionylation (PSSG) redox module in the regulation of ischaemic revascularization, indicating potential clinical and therapeutic applications.

Keywords: Bronchopulmonary dysplasia; Glutaredoxin; Hypoxia-inducible factor-1α; Nuclear factor-κB; Protein S-Glutathionylation; Vascular endothelial growth factor.