Sodium nitrite augments lung S-nitrosylation and reverses chronic hypoxic pulmonary hypertension in juvenile rats - PubMed (original) (raw)
. 2018 Nov 1;315(5):L742-L751.
doi: 10.1152/ajplung.00184.2018. Epub 2018 Aug 9.
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- PMID: 30091380
- DOI: 10.1152/ajplung.00184.2018
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Sodium nitrite augments lung S-nitrosylation and reverses chronic hypoxic pulmonary hypertension in juvenile rats
Robert P Jankov et al. Am J Physiol Lung Cell Mol Physiol. 2018.
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Abstract
Deficient nitric oxide (NO) signaling plays a critical role in the pathogenesis of chronic neonatal pulmonary hypertension (PHT). Physiological NO signaling is regulated by S-nitrosothiols (SNOs), which act both as a reservoir for NO and as a reversible modulator of protein function. We have previously reported that therapy with inhaled NO (iNO) increased peroxynitrite-mediated nitration in the juvenile rat lung, although having minimal reversing effects on vascular remodeling. We hypothesized that sodium nitrite (NaNO2) would be superior to iNO in enhancing lung SNOs, thereby contributing to reversal of chronic hypoxic PHT. Rat pups were exposed to air or hypoxia (13% O2) from postnatal days 1 to 21. Dose-response prevention studies were conducted from days 1-21 to determine the optimal dose of NaNO2. Animals then received rescue therapy with daily subcutaneous NaNO2 (20 mg/kg), vehicle, or were continuously exposed to iNO (20 ppm) from days 14-21. Chronic PHT secondary to hypoxia was both prevented and reversed by treatment with NaNO2. Rescue NaNO2 increased lung NO and SNO contents to a greater extent than iNO, without causing nitration. Seven lung SNO proteins upregulated by treatment with NaNO2 were identified by multiplex tandem mass tag spectrometry, one of which was leukotriene A4 hydrolase (LTA4H). Rescue therapy with a LTA4H inhibitor, SC57461A (10 mg·kg-1·day-1 sc), partially reversed chronic hypoxic PHT. We conclude that NaNO2 was superior to iNO in increasing tissue NO and SNO generation and reversing chronic PHT, in part via upregulated SNO-LTA4H.
Keywords: cofilin; leukotriene; newborn; nitration; nitric oxide.
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