Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1.

Abstract

Although previous studies have shown that flutamide improves cardiovascular function after trauma-hemorrhage, 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-gamma 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 (COX) subunit I, II, and III (COX I, COX II, and COX III), which regulates mitochondrial oxidative phosphorylation. To test this hypothesis, male rats underwent trauma-hemorrhage (mean arterial pressure of 35-40 mmHg for approximately 90 min) followed by resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg body wt), flutamide in combination with estrogen receptor (ER) antagonist ICI-182,780 (3 mg/kg body wt), or ICI-182,780 alone. Flutamide administration after trauma-hemorrhage restored the depressed cardiac function and increased cardiac testosterone, estrogen levels, and aromatase activity. These increases were accompanied by normalized cardiac ER-alpha and ER-beta protein levels, PGC-1, and COX I mRNA expression, mitochondrial COX activity, and ATP contents. However, cardiac dihydrotestosterone, 5alpha-reductase II, androgen receptor protein levels, and mtDNA-encoded genes COX II and COX III were unaffected by flutamide treatment. The flutamide-mediated restoration of cardiac function, the increases in aromatase activity and estrogen levels, ER-alpha, ER-beta, PGC-1, COX I, COX 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 after trauma-hemorrhage is mediated via an estrogen-dependent pathway through upregulation of PGC-1.

• Authors: Ya-Ching Hsieh, Shaolong Yang, Mashkoor A Choudhry, Huang-Ping Yu, Kirby I Bland, Martin G Schwacha, Irshad H Chaudry
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 290 Issue 1 Pg. H416-23 (Jan 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16155096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Estrogen Antagonists
• Receptors, Estrogen
• Transcription Factors
• peroxisome-proliferator-activated receptor-gamma coactivator-1
• Dihydrotestosterone
• Fulvestrant
• Testosterone
• Estradiol
• Flutamide
• Aromatase
• Electron Transport Complex IV

Topics

• Abdominal Injuries (physiopathology)
• Animals
• Aromatase (metabolism)
• Dihydrotestosterone (analysis)
• Electron Transport Complex IV (biosynthesis)
• Estradiol (analogs & derivatives, analysis, pharmacology, physiology)
• Estrogen Antagonists (pharmacology)
• Flutamide (pharmacology)
• Fulvestrant
• Heart Function Tests
• Hemorrhage (physiopathology)
• Male
• Myocardium (chemistry, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Estrogen (biosynthesis)
• Testosterone (analysis)
• Transcription Factors (biosynthesis)
• Up-Regulation