| PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage. | |
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MedLine Citation:
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PMID: 16055512 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Ya-Ching Hsieh; Shaolong Yang; Mashkoor A Choudhry; Huang-Ping Yu; Loring W Rue; Kirby I Bland; Irshad H Chaudry |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2005-07-29 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 289 ISSN: 0363-6135 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2005 Dec |
Date Detail:
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Created Date: 2005-11-14 Completed Date: 2006-01-10 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H2665-72 Citation Subset: IM |
Affiliation:
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Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cardiotonic Agents / administration & dosage Estradiol / administration & dosage* Flutamide / administration & dosage* Heart / drug effects, physiopathology* Hemorrhage / drug therapy*, etiology, physiopathology* Male Rats Rats, Sprague-Dawley Receptors, Estrogen / metabolism* Recovery of Function / drug effects, physiology Transcription Factors / metabolism* Treatment Outcome Up-Regulation / drug effects Wounds, Penetrating / complications, drug therapy, physiopathology* |
| Grant Support | |
ID/Acronym/Agency:
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R37 GM-39519/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Receptors, Estrogen; 0/Transcription Factors; 0/peroxisome-proliferator-activated receptor-gamma coactivator-1; 13311-84-7/Flutamide; 50-28-2/Estradiol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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