Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Acknowledgments
  • Footnotes
  • References
  • Version history
Article has an altmetric score of 2

See more details

Posted by 5 X users
3 readers on Mendeley
  • Article usage
  • Citations to this article (0)

Advertisement

100th Anniversary Viewpoints Open Access | 10.1172/JCI176253

Clinical investigation of hypoxia-inducible factors: getting there

Gregg L. Semenza

Armstrong Oxygen Biology Research Center, Institute for Cell Engineering, and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Gregg L. Semenza, Johns Hopkins University School of Medicine, Institute for Cell Engineering, Miller Research Building, Suite 671, 733 North Broadway, Baltimore, Maryland 21205, USA. Email: gsemenza@jhmi.edu.

Find articles by Semenza, G. in: JCI | PubMed | Google Scholar |

Published February 1, 2024 - More info

Published in Volume 134, Issue 3 on February 1, 2024
J Clin Invest. 2024;134(3):e176253. https://doi.org/10.1172/JCI176253.
© 2024 Semenza 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/.
Published February 1, 2024 - Version history
View PDF

As part of the JCI’s 100th-anniversary celebration, I reflect here on a few of the many papers published in JCI that have advanced our understanding of the physiological and pathological responses to hypoxia, with an emphasis on the hypoxia-inducible factors (HIFs), which mediate transcriptional responses to decreased O2 availability. HIFs consist of an O2-labile HIF-1α, HIF-2α, or HIF-3α subunit and a constitutively expressed HIF-1β (also known as ARNT) subunit. The HIF prolyl hydroxylases use O2 and α-ketoglutarate as substrates to modify the HIF-α subunits by inserting an oxygen atom into a prolyl residue (either P402 or P564 in human HIF-1α) under normoxic conditions; the hydroxylated proteins are selectively bound by the von Hippel–Lindau tumor suppressor protein (VHL), which recruits a ubiquitin-protein ligase that ubiquitinates the HIF-α subunits, thereby marking them for proteasomal degradation (1). In contrast, under hypoxic conditions, the hydroxylases are inhibited and HIF-α subunits rapidly accumulate, providing a direct mechanism to transduce changes in O2 availability to changes in HIF activity (1). I also briefly highlight the role of HIFs in erythropoiesis, pulmonary vascular biology, angiogenesis, metabolism, cancer, and diabetic eye diseases.

In 1999, my group reported that mice, which were heterozygous for a knockout allele at the locus encoding HIF-1α, manifested impaired responses to chronic hypoxia (exposure to a 10% O2 ambient environment for 3 weeks) (2). The reason for studying heterozygotes was that the homozygotes, which completely lacked HIF-1α expression, died at midgestation, with defects in heart development, tissue vascularization, and red blood cell production, thereby demonstrating that HIF-1α was required for development of all three components of the circulatory system. Analysis of the heterozygotes provided a connection between the role of HIF-1 in development and its role in physiology. Mice exposed to chronic hypoxia develop erythrocytosis and pulmonary hypertension, and these responses were impaired in the heterozygotes. The effect on erythrocytosis remains unexplained; HIF-2 is now considered the primary regulator of adult erythropoiesis through its regulation of EPO production, based on studies of conditional knockout mice (3) and studies demonstrating that missense mutations in the HIF pathway that increase HIF-2α expression result in the phenotypic triad of hereditary erythrocytosis, pulmonary hypertension, and thrombosis in humans and mice (4).

Hypoxic pulmonary vasoconstriction associated with lobar pneumonia is an adaptive response to hypoxia, as it shunts blood away from areas of lung that are not ventilated, whereas panlobar vasoconstriction is a maladaptive response to ambient hypoxia, as it leads to decreased blood oxygenation. Mice heterozygous for a HIF-2α–knockout allele were also protected from the development of pulmonary hypertension (5). The roles of HIF-1 and HIF-2 signaling in the pathogenesis of pulmonary hypertension are broad and essential, with complex feed-forward circuits, both within and between, pulmonary artery endothelial and smooth muscle cells, as delineated in an excellent review (6), which also discussed pharmacologic targeting of HIFs as a potential therapy in this disorder. The critical role of HIF-1 in the vascular response of lung transplants to chronic rejection was also established by a JCI paper; data from a mouse model suggested that adenoviral stimulation of HIF activity could prevent lung transplant rejection by maintaining integrity of the microvasculature and tissue perfusion during chronic rejection (7).

Hypoxia induces the HIF-dependent expression of angiogenic growth factors, such as VEGFA, which stimulate new blood vessel formation, thereby increasing tissue perfusion and oxygenation (8). One of the early studies demonstrating that VEGFA administration could augment ischemia-induced vascularization was published in JCI (9). Unfortunately, the study utilized young and previously healthy mice, which are not a suitable model for ischemic cardiovascular disease, which is a disease associated with aging. It took the field a long time to learn this lesson.

Two of the most critical adaptations to localized tissue hypoxia are the increased production of angiogenic growth factors to stimulate new blood vessel formation as a means to increase O2 delivery and the switch from oxidative to glycolytic metabolism as a means to decrease O2 consumption (10). The co-option of these physiological responses by cancer cells is best illustrated by the clear cell renal cell carcinoma (ccRCC) in patients with the von Hippel–Lindau syndrome, in which one copy of the VHL gene is inactivated by germline mutation and the other by somatic mutation within kidney cells. It is a peculiarity of this particular cancer that during tumor progression many ccRCCs lose HIF-1α expression and are driven solely by dysregulated HIF-2α expression; this led to the development of belzutifan, a drug that selectively binds to HIF-2α and blocks its dimerization with HIF-1β, thereby causing loss of HIF-2 transcriptional activity and a dramatic therapeutic benefit in patients with advanced ccRCC whose prognosis was previously bleak (11).

Among its many effects in breast cancer, HIF-1 was recently shown to control the production of small extracellular vesicles, which were shown to drive cancer progression via multiple mechanisms (12).

Another major recent advance has been the discovery that HIFs play critical roles in mediating the ability of cancer cells of many types, including breast, colorectal, and liver cancer, to evade killing by the immune system and that small-molecule inhibitors of HIF-1 and HIF-2 dramatically improve the response to immune checkpoint inhibitors (anti-CTLA4, anti–PD-1 or anti–PD-L1 antibody) in mouse models (13, 14). These HIF inhibitors have been remarkably well tolerated in mouse models, with no changes in mouse appearance, behavior, or body weight, suggesting that a therapeutic window exists for HIF inhibition, but, of course, this issue can only be definitively resolved by clinical trials.

Diabetic eye disease is a major and increasing cause of progressive vision loss and blindness in the adult US population. Both HIF-1 and HIF-2 play major roles in retinal neovascularization, and, in mouse models, a small-molecule dual HIF-1/HIF-2 inhibitor safely and effectively blocks the development of macular edema and ischemic retinal neovascularization, which are the causes of vision loss associated with diabetes (15). These studies have highlighted that a large battery of angiogenesis-associated gene products are expressed in a HIF-dependent manner in diabetic eye diseases and that, whereas current therapies target only one of them (VEGFA), HIF inhibitors have a much broader effect on gene expression, which may translate into a higher response rate among patients with diabetic eye diseases, less than half of whom respond well to anti-VEGFA therapies (15). Because drugs for these conditions are delivered by intraocular injection, systemic adverse effects are not a major consideration.

The last quarter of the JCI’s first century has seen dramatic advances in our understanding of the role of HIFs in the pathogenesis of diseases, with major effects on morbidity and mortality. Looking forward, I anticipate that further pharmacologic targeting of HIFs will provide therapeutic benefit in several of these disorders. Table 1 lists the approved and some of the potential therapeutic applications for pharmacologic HIF inducers and HIF inhibitors. Let’s hope to see more patients replace mice as the recipients of novel therapies in the JCI. Watch this space.

Table 1

Approved and potential therapeutic targets for small-molecule HIF inducers and HIF inhibitors

Acknowledgments

GLS is the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. Research in GLS’s laboratory is supported by the Armstrong Family Foundation.

Address correspondence to: Gregg L. Semenza, Johns Hopkins University School of Medicine, Institute for Cell Engineering, Miller Research Building, Suite 671, 733 North Broadway, Baltimore, Maryland 21205, USA. Email: gsemenza@jhmi.edu.

Footnotes

Conflict of interest: GLS is an inventor on provisional patent application US/63,231,216 and is a founder of, and holds equity in, HIF Therapeutics Inc. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies.

Copyright: © 2024, Semenza. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information:J Clin Invest. 2024;134(3):e176253. https://doi.org/10.1172/JCI176253.

References
  1. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123(9):3664–3671.
    View this article via: JCI CrossRef PubMed Google Scholar
  2. Yu AY, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. J Clin Invest. 1999;103(5):691–696.
    View this article via: JCI CrossRef PubMed Google Scholar
  3. Rankin EB, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117(4):1068–1077.
    View this article via: JCI CrossRef PubMed Google Scholar
  4. Hickey MM, et al. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest. 2010;120(3):827–839.
    View this article via: JCI CrossRef PubMed Google Scholar
  5. Brusselmans K, et al. Heterozygous deficiency of hypoxia-inducible factor-2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest. 2003;111(10):1519–1527.
    View this article via: JCI CrossRef PubMed Google Scholar
  6. Pullamsetti SS, et al. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest. 2020;130(11):5638–5651.
    View this article via: JCI CrossRef PubMed Google Scholar
  7. Jiang X, et al. Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. J Clin Invest. 2011;121(6):2336–2349.
    View this article via: JCI CrossRef PubMed Google Scholar
  8. Semenza GL. Series introduction: tissue ischemia: pathophysiology and therapeutics. J Clin Invest. 2000;106(5):613–614.
    View this article via: JCI CrossRef PubMed Google Scholar
  9. Takeshita S, et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994;93(2):662–670.
    View this article via: JCI CrossRef PubMed Google Scholar
  10. De Heer EC, et al. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020;130(10):5074–5087.
    View this article via: JCI CrossRef PubMed Google Scholar
  11. Chappell JC, et al. Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers. J Clin Invest. 2019;129(2):442–451.
    View this article via: JCI CrossRef PubMed Google Scholar
  12. Bertolini I, et al. Intercellular HIF1α reprograms mammary progenitors and myeloid immune evasion to drive high-risk breast lesions. J Clin Invest. 2023;133(8):e164348.
    View this article via: JCI CrossRef PubMed Google Scholar
  13. Bailey CM, et al. Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues. J Clin Invest. 2022;132(9):e150846.
    View this article via: JCI CrossRef PubMed Google Scholar
  14. Salman S, et al. HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy. J Clin Invest. 2022;132(9):e156774.
    View this article via: JCI CrossRef PubMed Google Scholar
  15. Zhang J, et al. Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice. J Clin Invest. 2023;133(13):e163290.
    View this article via: JCI CrossRef PubMed Google Scholar
Version history
  • Version 1 (February 1, 2024): Electronic publication

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Related Collection:

JCI's 100th anniversary
  • Solid organ transplantation: solid but not yet spectacular
    Laurence A. Turka
  • Leptin physiology and pathophysiology: knowns and unknowns 30 years after its discovery
    Jeffrey S. Flier et al.
  • The GLP-1 journey: from discovery science to therapeutic impact
    Daniel J. Drucker
  • CAR T cells for hematological malignancies
    Barbara Savoldo et al.
  • Pancreatic β cell function versus insulin resistance: application of the hyperbolic law of glucose tolerance
    Richard N. Bergman
  • Nitric oxide in vascular biology: elegance in complexity
    Joseph Loscalzo
  • How the JCI’s most-cited paper sparked the field of lipoprotein research
    Michael S. Brown et al.
  • SGLT2 inhibitors: cardiorenal metabolic drugs for the ages
    Ralph A. DeFronzo
  • G protein–coupled receptors: from radioligand binding to cellular signaling
    Howard A. Rockman et al.
  • Bisphosphonates for osteoporosis: from bench to clinic
    Teresita Bellido
  • Pandemics past, present, and future: progress and persistent risks
    Arturo Casadevall
  • Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation
    Leslie S. Kean et al.
  • Life-saving effect of pulmonary surfactant in premature babies
    J. Usha Raj et al.
  • Advancing chemokine research: the molecular function of CXCL8
    Yiran Hou et al.
  • Navigating an enigma: the continuing journey of autoimmunity discoveries
    Mariana J. Kaplan
  • Defining and targeting mechanisms of eosinophilic inflammation in a new era of severe asthma treatment
    Joshua A. Boyce et al.
  • The other pandemic: lessons from 40 years of HIV research
    Mary E. Klotman et al.
  • A half-century of VEGFA: from theory to practice
    Susan E. Quaggin
  • Two decades of advances in preeclampsia research: molecular mechanisms and translational studies
    S. Ananth Karumanchi
  • The forgotten pandemic: how understanding cholera illuminated mechanisms of chloride channels in multiple diseases
    Qais Al-Awqati
  • Is it time to rethink the relationship between adipose inflammation and insulin resistance?
    Evan D. Rosen et al.
  • Checkpoint therapy in cancer treatment: progress, challenges, and future directions
    Mesude Bicak et al.
  • The arc of discovery, from the description of cystic fibrosis to effective treatments
    Michael J. Welsh
  • Intertwining clonality and resistance: Staphylococcus aureus in the antibiotic era
    Henry F. Chambers et al.
  • The expanding application of antisense oligonucleotides to neurodegenerative diseases
    Charlotte J. Sumner et al.
  • Toward a better understanding of chronic hepatitis B virus infection
    Barbara Rehermann
  • The convergence of genomic medicine and translational omics in transforming breast cancer patient care
    Sulin Wu et al.

Metrics

Article has an altmetric score of 2
  • Article usage
  • Citations to this article (0)

Go to

  • Top
  • Acknowledgments
  • Footnotes
  • References
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 5 X users
3 readers on Mendeley
See more details