ArticleProceedings of the National Academy of Sciences of the United States of America2011
Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 74 citations in OpenAlex.
- Differential effects of phenylephrine on brain versus skeletal muscle microvascular perfusion: an in vivo laboratory study using translational rodent models.Canadian journal of anaesthesia = Journal canadien d'anesthesie · 2026Article
- Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics-a narrative review.Critical care (London, England) · 2024Review
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- Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure.The Journal of clinical investigation · 2023Article
- S-Nitroso-l-cysteine and ventilatory drive: A pediatric perspective.Pediatric pulmonology · 2022Review
- Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy.Cardiovascular drugs and therapy · 2022Article
- Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration.Free radical biology & medicine · 2021Review
- Molecular Characterization and Expression of Cytochrome P450 Aromatase in Atlantic Croaker Brain: Regulation by Antioxidant Status and Nitric Oxide Synthase During Hypoxia Stress.Frontiers in physiology · 2021Article
- Protective effect of dipeptidyl peptidase-4 inhibitors in testicular torsion/detorsion in rats: a possible role of HIF-1α and nitric oxide.Naunyn-Schmiedeberg's archives of pharmacology · 2020Article
- Sirtuin 1 activation attenuates cardiac fibrosis in a rodent pressure overload model by modifying Smad2/3 transactivation.Cardiovascular research · 2018Article
- Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain.American journal of physiology. Regulatory, integrative and comparative physiology · 2018Article
- Experimental assessment of oxygen homeostasis during acute hemodilution: the integrated role of hemoglobin concentration and blood pressure.Intensive care medicine experimental · 2017Article
- Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression.Antioxidants & redox signaling · 2017Review
- Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- Association between hypoxemia and anemia following arthroplasty: A pilot clinical study.Experimental and therapeutic medicine · 2016Article
- Article
- Review
- Is methemoglobin an inert bystander, biomarker or a mediator of oxidative stress--The example of anemia?Redox biology · 2013Review
- S-nitrosylation: integrator of cardiovascular performance and oxygen delivery.The Journal of clinical investigation · 2013Review
- Nitric oxide signaling in hypoxia.Journal of molecular medicine (Berlin, Germany) · 2012Review
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS)(-/-) mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS(-/-) mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS(-/-) mice, despite comparable reductions in tissue PO(2). Paradoxically, nNOS(-/-) mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S-nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S-nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.