Document Detail

PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage.
MedLine Citation:
PMID:  16055512     Owner:  NLM     Status:  MEDLINE    
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.
Ya-Ching Hsieh; Shaolong Yang; Mashkoor A Choudhry; Huang-Ping Yu; Loring W Rue; Kirby I Bland; Irshad H Chaudry
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2005-07-29
Journal Detail:
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:
Created Date:  2005-11-14     Completed Date:  2006-01-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2665-72     Citation Subset:  IM    
Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA.
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MeSH Terms
Cardiotonic Agents / administration & dosage
Estradiol / administration & dosage*
Flutamide / administration & dosage*
Heart / drug effects,  physiopathology*
Hemorrhage / drug therapy*,  etiology,  physiopathology*
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
Reg. No./Substance:
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

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