PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage.
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.
Hsieh
Ya-Ching
YC
Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA.
Yang
Shaolong
S
Choudhry
Mashkoor A
MA
Yu
Huang-Ping
HP
Rue
Loring W
LW
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004958:Estradiol / Q000008:administration & dosage*; D005485:Flutamide / Q000008:administration & dosage*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D014950:Wounds, Penetrating / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*
D002316:Cardiotonic Agents; D011960:Receptors, Estrogen; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D004958:Estradiol; D005485:Flutamide