期刊
CELL BIOLOGY INTERNATIONAL
卷 47, 期 4, 页码 796-807出版社
WILEY
DOI: 10.1002/cbin.11985
关键词
BPD; Grx1; HIF-1 alpha; S-glutathionylation; VEGF
类别
HIF-1 alpha stabilization has a critical role in modifying pulmonary microcirculatory perfusion, which is important in the pathogenesis of BPD. This study investigated the modulation of HIF-1 alpha stabilization through Grx1 ablation and its effects on the pathology of BPD in a mouse model. The results showed that Grx1 ablation increased levels of GSH-protein adducts, leading to improvements in alveolar numbers, capillary density, and survival rate. These effects were mediated through HIF-1 alpha glutathionylation and VEGF-A production in the lung tissue.
Hypoxia inducible factor (HIF)-1 alpha could be stabilized by Grx1 deletion, which is implicated critical in the pathogenesis of bronchopulmonary dysplasia (BPD). Until now, the stabilization of HIF-1 alpha by glutathionylation to regulate the pulmonary microcirculation in BPD is not well addressed. In this study, we investigated whether the HIF-1 alpha stabilization modulated by Grx1 ablation could ameliorate the pathological changes in the mouse model of BPD, including angiogenesis and alveolar formation. We found that depletion of Grx1 increased levels of GSH-protein adducts, which was associated with the improvement in the numbers of alveoli, the capillary density in the pulmonary microcirculation and the survival rate in the littermates with hyperoxic exposure. Grx1 ablation could promote HIF-1 alpha glutathionylation by increasing GSH adducts to stabilize HIF-1 alpha and to induce VEGF-A production in the lung tissue. The above phenotype of capillary density and VEGF-A production was removed by the pharmacological administration of YC-1, the HIF-1 alpha inhibitor, suggesting the HIF-1 alpha dependent manner for pulmonary microcirculatory perfusion. These data indicate that HIF-1 alpha stabilization plays an critical role in modification pulmonary microcirculatory perfusion, which is associated with the pathological damage under hyperoxic conditions, suggesting that targeting with HIF-1 alpha stabilization should be a potential clinical and therapeutic strategy for BPD treatment.
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