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Hypoxia-Inducible Factor-1α (HIF-1α) Modulation as a Strategy to Prevent Ischemic Cell Injury in the Heart

Wei Zhang, PhD, Min Li, PhD, Rui Chen, PhD1*

1 Department of Cardiovascular Physiology, Cardiovascular Research Institute, Nanjing Medical University, Nanjing, Jiangsu, China

DOI: 10.18081/pcij/2378-5225/016-06/1-15                Cited by icon Cited by 0 OpenAlex Scholar Crossref

 

Article history: Received 15 Dec 2024 · Revised 15 Dec 2025 · Accepted 02 May 2025 · Published 09 Jun 2025

© 2025 Chen, ed at. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). 

CC BY 4.0                                                                                                   

Abstract

Background: Ischemia–reperfusion (I/R) injury remains a critical determinant of myocardial infarction outcomes, leading to irreversible cardiomyocyte death despite successful reperfusion. The transcription factor Hypoxia-Inducible Factor-1α (HIF-1α) is a central regulator of oxygen homeostasis and cellular adaptation to hypoxia. However, the therapeutic window, mechanistic pathways, and translational potential of HIF-1α modulation in cardioprotection require further investigation.

Methods: This experimental study employed in vitro hypoxia/reoxygenation of H9c2 cardiomyocytes and in vivo rat models of myocardial I/R injury. Pharmacologic modulators of HIF-1α were used: dimethyloxalylglycine (DMOG) and roxadustat (FG-4592) as stabilizers, and YC-1 as an inhibitor. HIF-1α expression and downstream targets (VEGF, BNIP3, HO-1) were assessed by Western blotting and qPCR. Myocardial infarct size, apoptosis, mitochondrial function, and oxidative stress markers (ROS, MDA, SOD) were quantified. The involvement of PI3K/AKT/Nrf2 signaling was evaluated to elucidate mechanistic pathways.

Results: HIF-1α stabilization via DMOG and roxadustat significantly reduced infarct size (22.4 ± 2.6% and 25.7 ± 2.8%, respectively; p < 0.001 vs. I/R), lowered serum CK-MB, LDH, and cTnI, and decreased cardiomyocyte apoptosis. Both agents enhanced the Bcl-2/Bax ratio, preserved mitochondrial membrane potential, and attenuated oxidative stress. These effects were accompanied by increased VEGF, BNIP3, and HO-1 expression and activation of the PI3K/AKT/Nrf2 axis. Inhibition of HIF-1α by YC-1 reversed these benefits, confirming its pivotal role in cytoprotection.

Conclusions: Pharmacologic activation of HIF-1α confers significant cardioprotection against ischemia–reperfusion injury through anti-apoptotic, antioxidant, and mitochondrial-stabilizing mechanisms. Controlled HIF-1α modulation—particularly via clinically relevant agents such as roxadustat—represents a promising therapeutic strategy to reduce myocardial ischemic injury and improve post-infarction recovery.

Keywords: HIF-1α; Ischemia–Reperfusion Injury; Cardiomyocytes; Roxadustat; Dimethyloxalylglycine; Mitochondrial Integrity

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BM-Publisher · Pathophysiology of Cell Injury Journal (PCIJ) · E-ISSN 2378-5225 · DOI Prefix 10.18081/2378-5225

Pathophysiology of Cell Injury Journal (PCIJ)
E-ISSN 2378-5225 · Biannual
BM-Publisher (London, UK)
Open Access

Vol 14, Issue 1 (June 2025), pp. 1–17

How to cite (AMA)

Zhang W, Li M, Chen R. Hypoxia-Inducible Factor-1α (HIF-1α) Modulation as a Strategy to Prevent Ischemic Cell Injury in the Heart. Pathophysiology of Cell Injury Journal (PCIJ). 2015;5(1):1–15. doi: 10.18081/pcij/2378-5225/016-06/1-17.

More citation

Wei Zhang, M. L. R. C. (2025). . Pathophysiology of Cell Injury Journal (PCIJ), 14(1), 1–17. https://doi.org/10.18081/pcij/2378-5225/14/1-17
Wei Zhang, Min Li, Rui Chen. \".\" Pathophysiology of Cell Injury Journal (PCIJ), vol. 14, no. 1, 2025, pp. 1–17. https://doi.org/10.18081/pcij/2378-5225/14/1-17
Wei Zhang, Min Li, Rui Chen. . Pathophysiology of Cell Injury Journal (PCIJ). 2025;14(1):1–17. doi:10.18081/pcij/2378-5225/14/1-17
Wei Zhang, Min Li, Rui Chen (2025) . Pathophysiology of Cell Injury Journal (PCIJ), 14(1), pp. 1–17. doi: 10.18081/pcij/2378-5225/14/1-17
@article{wei-zhang-min-li-rui-chen-2025, title = {}, author = {Wei Zhang, Min Li, Rui Chen}, journal = {Pathophysiology of Cell Injury Journal (PCIJ)}, year = {2025}, volume = {14}, number = {1}, pages = {1–17}, doi = {10.18081/pcij/2378-5225/14/1-17}, url = {https://pcij.net/archives/1572}, }
TY - JOUR AU - Wei Zhang, Min Li, Rui Chen TI - JO - Pathophysiology of Cell Injury Journal (PCIJ) PY - 2025 VL - 14 IS - 1 SP - 1–17 DO - 10.18081/pcij/2378-5225/14/1-17 UR - https://pcij.net/archives/1572 ER -

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