Flutamide Restores Cardiac Functions following Trauma- Hemorrhage via an Estrogen-dependent Pathway through Upregulation of Pgc-1

Although previous studies have shown that flutamide improves cardiovascular functions following trauma-hemorrhage (T-H), the mechanisms responsible for the salutary effect remain unknown. We hypothesized that flutamide mediates its beneficial effects via an estrogen-dependent pathway through upregulation of peroxisome proliferator-activated receptor coactivator-1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial ATP production, induces mitochondrial DNA (mtDNA)-encoded genes such as cytochrome c oxidase subunit I, II, and III (CO I, II, and CO III), which regulates mitochondrial oxidative phosphorylation. To test this hypothesis, male rats underwent T-H (MAP 35-40 mmHg for ~ 90 min) followed by resuscitation. At the onset of resuscitation, rats received either vehicle, flutamide (25 mg/kg BW), flutamide in combination with estrogen receptor (ER) antagonist ICI 182,780 (3 mg/kg BW), or ICI 182,780 alone. Flutamide administration following TH restored the depressed cardiac functions and increased cardiac testosterone, estrogen levels, and aromatase activity. These increases were accompanied with normalized cardiac ER-α and ER-β protein levels, PGC-1 and CO I mRNA expression, mitochondrial CO activity, and ATP contents. However, cardiac dihydrotestosterone (DHT), 5α-reductase II, and androgen receptor (AR) protein levels, and mtDNA-encoded genes CO II, CO III were unaffected by flutamide treatment. The flutamide-mediated restoration of cardiac functions, the increases in aromatase activity and estrogen levels, antagonist ICI 182,780 was administrated along with flutamide. These findings suggest that the salutary effect of flutamide on cardiac function following T-H is mediated via an estrogen-dependent pathway through upregulation of PGC-1.