Hypoxia-Inducible Factor-2α Transactivates Abcg2 and Promotes Cytoprotection in Cardiac Side Population Cells
Abstract
Stem and progenitor cell populations occupy a specialized niche and are consequently exposed to hypoxic as well as oxidative stresses. We have previously established that the multidrug resistance protein Abcg2 is the molecular determinant of the side population (SP) progenitor cell population. We observed that the cardiac SP cells increase in number more than 3-fold within 3 days of injury. Transcriptome analysis of the SP cells isolated from the injured adult murine heart reveals increased expression of cytoprotective transcripts. Overexpression of Abcg2 results in an increased ability to consume hydrogen peroxide and is associated with increased levels of alpha-glutathione reductase protein expression. Importantly, overexpression of Abcg2 also conferred a cell survival benefit following exposure to hydrogen peroxide. To further examine the molecular regulation of the Abcg2 gene, we demonstrated that hypoxia-inducible factor (HIF)-2alpha binds an evolutionary conserved HIF-2alpha response element in the murine Abcg2 promoter. Transcriptional assays reveal a dose-dependent activation of Abcg2 expression by HIF-2alpha. These results support the hypothesis that Abcg2 is a direct downstream target of HIF-2alpha which functions with other factors to initiate a cytoprotective program for this progenitor SP cell population that resides in the adult heart.
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HIF-2 can activate transcription of ABCG2, suggesting a potential mechanism of HIF2-induced chemoresistance.
“Similarly, HIF-2 can activate transcription of another ABC transporter ABCG2, suggesting a potential mechanism of HIF2-induced chemoresistance (Martin et al., 2008).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Martin et al., 2008
HIFs mediate chemoresistance.
“A number of studies suggest that HIFs mediate chemoresistance.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Martin et al., 2008
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References 33 · Cited by 133
- Authors
- Martin, C. M., Ferdous, A., Gallardo, T., Humphries, C., Sadek, H., Caprioli, A., Garcia, J. A., Szweda, L. I., Garry, M. G., & Garry, D. J.
- Affiliations
- University of Minnesota (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2008-05-09
- Volume
- 102
- Issue
- 9
- Pages
- 1075-1081
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2096234867
- Cited by
- 133
- References
- 33
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 9 · 2016: 8 · 2015: 8 · 2014: 9 · 2013: 10 · 2012: 12
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL067154)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Keywords
- HIF-2α, ABCG2, multidrug resistance protein, cardiac progenitor cells, cardiomyocyte injury, cytoprotection, hydrogen peroxide, transcriptional regulation, oxidative stress, cardiac regeneration
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Endothelial PAS Domain-Containing Protein 1, Animals, Cell Line, Cells, Cultured, Cold Temperature, Disease Models, Animal, Glutathione Reductase, Heart Injuries, Hydrogen Peroxide, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Time Factors, Transcription, Genetic, Transfection, Signal Transduction, Transcriptional Activation, Up-Regulation, Oxidative Stress, ATP-Binding Cassette Transporters, Cytoprotection, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Proliferation, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Embryonic Stem Cells, Adult Stem Cells
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