ArticleThe Journal of biological chemistry2016
Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 61 citations in OpenAlex.
- Timing the strain: skeletal muscle clock as regulator of physical activity.npj metabolic health and disease · 2026Review
- Aryl hydrocarbon receptor-dependent lipid droplet accumulation supports redox homeostasis in hypoxia-induced PCa cells.American journal of cancer research · 2026Article
- pH sensing and inflammation: linking acidic microenvironments to immune reprogramming.Frontiers in immunology · 2026Review
- Apnoea as a novel method to improve exercise performance: A current state of the literature.Experimental physiology · 2025Review
- Sensing molecular carbon dioxide: a translational focus for respiratory disease.Physiological reviews · 2025Review
- Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.The Journal of cell biology · 2025Article
- Hypoxia induced lipid droplet accumulation promotes resistance to ferroptosis in prostate cancer.Oncotarget · 2025Article
- Gene Expression Profiling of Pancreatic Ductal Adenocarcinoma Cells in Hypercapnia Identifies SIAH3 as a Novel Prognostic Biomarker.International journal of molecular sciences · 2025Article
- Effect of intermittent extracellular low-pH environment on human umbilical vein endothelial cell activity.PloS one · 2025Article
- Potential of a COMaterials today. Bio · 2024Article
- Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.International journal of molecular sciences · 2024Review
- Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia.International journal of molecular sciences · 2024Article
- Hypoxia, hypoxia-inducible factors and inflammatory bowel diseases.Gastroenterology report · 2024Review
- The Tissue Response to Hypoxia: How Therapeutic Carbon Dioxide Moves the Response toward Homeostasis and Away from Instability.International journal of molecular sciences · 2023Review
- A COPharmaceutics · 2023Article
- A framework of transient hypercapnia to achieve an increased cerebral blood flow induced by nasal breathing during aerobic exercise.Cerebral circulation - cognition and behavior · 2023Review
- The effect of HIF on metabolism and immunity.Nature reviews. Nephrology · 2022Review
- Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis.Frontiers in cell and developmental biology · 2022Review
- Influence of the Hypercapnic Tumor Microenvironment on the Viability of Hela Cells Screened by a COACS omega · 2021Article
- Ubiquitin is a carbon dioxide-binding protein.Science advances · 2021Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.
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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 OpenQuestion graph.