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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Abstract
Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17β-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 β-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for ∼90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 μg/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 β-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.