Pgc-1 upregulation Via estrogen receptors: A common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage
Abstract
Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17beta-estradiol (E2) and flutamide improve cardiac function after T-H, whether E2 and flutamide produce their salutary effect via the same or a different mechanism is unknown. We hypothesized that E2 and flutamide mediate their effects via estrogen receptor (ER)-mediated upregulation of peroxisome proliferator-activated receptor coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial function, induces mitochondrial genes by activating transcription factors such as nuclear respiratory factor 2 (NRF-2), which regulates mitochondrial proteins [i.e., mitochondrial transcription factor A (Tfam), cytochrome-c oxidase subunit IV, and beta-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for approximately 90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 microg/kg). Another group received the ER antagonist ICI-182780 (3 mg/kg) with or without flutamide. Flutamide or E2 administration after T-H restored depressed cardiac function. Moreover, E2 and flutamide normalized expression of cardiac PGC-1, NRF-2, Tfam, cytochrome-c oxidase subunit IV, and the mitochondrial DNA-encoded gene cytochrome-c oxidase subunit I and beta-ATP synthase, mitochondrial ATP, and cytochrome-c oxidase activity. However, if the ER antagonist ICI-182780 was administered with flutamide, flutamide-mediated PGC-1 upregulation was totally abolished. These results indicate that E2 and flutamide upregulate PGC-1 via the ER. Thus PGC-1 upregulation appears to be the common mechanism by which E2 and flutamide mediate their salutary effects on cardiac function after T-H.
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Estrogens upregulate the expression of PGC-1 and its downstream target genes via genomic ERα and ERβ to promote mitochondrial biogenesis and ATP production.
“For instance, estrogens upregulate the expression of PGC-1 and its downstream target genes via genomic ERα and ERβ to promote mitochondrial biogenesis and ATP production (121).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [121]
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- Authors
- Hsieh, Y.-C., Yang, S., Choudhry, M. A., Yu, H.-P., Rue, L. W., Bland, K. I., & Chaudry, I. H.
- Affiliations
- University of Alabama at Birmingham (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2005-12
- Volume
- 289
- Issue
- 6
- Pages
- H2665-H2672
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2011193031
- Cited by
- 84
- References
- 40
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 1 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 5
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R37GM039519, R37 GM39519)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- PGC-1, estrogen receptor, flutamide, estradiol, traumatic hemorrhage, cardiac function, mitochondrial function, Nrf2, TFAM, cytochrome c oxidase, fulvestrant, androgen receptor antagonists, cardioprotection, resuscitation
- MeSH terms
- Animals, Cardiotonic Agents, Estradiol, Flutamide, Heart, Hemorrhage, Male, Receptors, Estrogen, Transcription Factors, Wounds, Penetrating, Up-Regulation, Treatment Outcome, Rats, Sprague-Dawley, Recovery of Function, Rats
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