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Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control
Xiaotong Cheng, … , Tammie Bishop, Peter J. Ratcliffe
Xiaotong Cheng, … , Tammie Bishop, Peter J. Ratcliffe
Published January 30, 2020
Citation Information: J Clin Invest. 2020;130(5):2237-2251. https://doi.org/10.1172/JCI133194.
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Research Article

Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control

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Abstract

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.

Authors

Xiaotong Cheng, Maria Prange-Barczynska, James W. Fielding, Minghao Zhang, Alana L. Burrell, Joanna D.C.C. Lima, Luise Eckardt, Isobel L.A. Argles, Christopher W. Pugh, Keith J. Buckler, Peter A. Robbins, Emma J. Hodson, Richard K. Bruick, Lucy M. Collinson, Fraydoon Rastinejad, Tammie Bishop, Peter J. Ratcliffe

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Figure 1

PT2385 ablates ventilatory acclimatization to hypoxia in WT male mice.

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PT2385 ablates ventilatory acclimatization to hypoxia in WT male mice.
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(A) Graphs show changes in minute ventilation in response to an acute (5 minutes) challenge with 10% O2/3% CO2 (white bars) in male mice before (baseline) and following twice daily treatment with 10 mg/kg PT2385 (or vehicle), beginning 24 hours before 7-day exposure to hypoxia (H, 10% oxygen) and continuing throughout (to a total of 8 days of treatment) (n = 6). (B) Graph shows AVRs to challenges with 10% O2/3% CO2, quantified from the minute ventilation shown in A. Data were analyzed by 2-way repeated measures ANOVA with baseline recordings removed from the statistical analysis (P values in Table 1), followed by Holm-Sidak’s multiple comparisons 2-tailed test for individual time point comparisons, for which significance is reported in the graph. ****P < 0.0001.

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

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