title: 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.affiliation: Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 Univ. Boulevard, Birmingham Alabama 35294-0019, USA.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Shaolong
authors.initials: S
authors.lastname: Yang
authors.forename: Mashkoor A
authors.initials: MA
authors.lastname: Choudhry
authors.forename: Huang-Ping
authors.initials: HP
authors.lastname: Yu
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Martin G
authors.initials: MG
authors.lastname: Schwacha
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
mesh_terms: D000007:Abdominal Injuries / Q000503:physiopathology*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D013196:Dihydrotestosterone / Q000032:analysis; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D004958:Estradiol / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology*; D000077267:Fulvestrant; D006334:Heart Function Tests; D006470:Hemorrhage / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000096:biosynthesis; D013739:Testosterone / Q000032:analysis; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D013196:Dihydrotestosterone; D000077267:Fulvestrant; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D001141:Aromatase; D003576:Electron Transport Complex IV