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1 Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: Irshad.Chaudry{at}ccc.uab.edu.
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 (MBP 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-
and ER-
protein levels, PGC-1 and CO I mRNA expression, mitochondrial CO activity, and ATP contents. However, cardiac dihydrotestosterone (DHT), 5-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, ER-, ER-, PGC-1, CO I, CO activity, and ATP contents were, however, abolished when ER 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.
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