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Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation
Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O(2) sensor and O(2)-responsive NO signal transducer to r...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855790/ https://www.ncbi.nlm.nih.gov/pubmed/34914637 http://dx.doi.org/10.1172/jci.insight.155234 |
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author | Zhang, Rongli Hausladen, Alfred Qian, Zhaoxia Liao, Xudong Premont, Richard T. Stamler, Jonathan S. |
author_facet | Zhang, Rongli Hausladen, Alfred Qian, Zhaoxia Liao, Xudong Premont, Richard T. Stamler, Jonathan S. |
author_sort | Zhang, Rongli |
collection | PubMed |
description | Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O(2) sensor and O(2)-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian Hbs, β-globin cysteine93 (βCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during O(2) delivery. βCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting O(2) normally. Here, we show that βCys93Ala mutant mice had reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion and that hypoxic vasodilation by RBCs was impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, βCys93Ala mutant mice showed marked impairment of hypoxic peripheral vasodilation and developed signs of pulmonary hypertension with age. Mutant mice also died prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low O(2). Altogether, we identify a major role for RBC SNO in clinically relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle. |
format | Online Article Text |
id | pubmed-8855790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-88557902022-02-22 Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation Zhang, Rongli Hausladen, Alfred Qian, Zhaoxia Liao, Xudong Premont, Richard T. Stamler, Jonathan S. JCI Insight Research Article Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O(2) sensor and O(2)-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian Hbs, β-globin cysteine93 (βCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during O(2) delivery. βCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting O(2) normally. Here, we show that βCys93Ala mutant mice had reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion and that hypoxic vasodilation by RBCs was impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, βCys93Ala mutant mice showed marked impairment of hypoxic peripheral vasodilation and developed signs of pulmonary hypertension with age. Mutant mice also died prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low O(2). Altogether, we identify a major role for RBC SNO in clinically relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle. American Society for Clinical Investigation 2022-02-08 /pmc/articles/PMC8855790/ /pubmed/34914637 http://dx.doi.org/10.1172/jci.insight.155234 Text en © 2022 Zhang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhang, Rongli Hausladen, Alfred Qian, Zhaoxia Liao, Xudong Premont, Richard T. Stamler, Jonathan S. Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title | Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title_full | Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title_fullStr | Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title_full_unstemmed | Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title_short | Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation |
title_sort | hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 s-nitrosylation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855790/ https://www.ncbi.nlm.nih.gov/pubmed/34914637 http://dx.doi.org/10.1172/jci.insight.155234 |
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