Inhibition of cardiac PGC-1alpha expression abolishes ERbeta agonist-mediated cardioprotection following trauma-hemorrhage.
PGC-1alpha (peroxisome proliferator-activated receptor [PPARgamma] coactivator-1alpha) activates PPARalpha and mitochondrial transcription factor A (Tfam), which regulate proteins, fatty acid and ATP metabolism (i.e., FAT/CD36, MCAD, and COX I). Recently we found that the salutary effects of estradiol (E2) on cardiac function following trauma-hemorrhage (T-H) are mediated via estrogen receptor (ER)beta. In this study we tested the hypothesis that ERbeta-mediated cardioprotection is induced via up-regulation of PGC-1alpha through PPARalpha or Tfam-dependent pathway. Male rats underwent T-H and received ERalpha agonist propylpyrazole-triol (PPT), ERbeta agonist diarylpropionitrile (DPN), E2, or vehicle. Another group was treated with antisense PGC-1alpha oligonucleotides prior to administration of DPN. E2 and DPN treatments attenuated the decrease in cardiac mitochondrial ATP, abrogated the T-H-induced lipid accumulation, and normalized PGC-1alpha, PPARalpha, FAT/CD36, MCAD, Tfam, and COX I after T-H. In contrast, PPT administration did not abrogate lipid accumulation. Moreover, in PPT-treated animals mitochondrial ATP remained significantly lower than those observed in DPN- or E2-treated animals. Prior administration of antisense PGC-1alpha prevented DPN-mediated cardioprotection and increase in ATP levels and Tfam but not in PPARalpha following T-H. These findings suggest that the salutary effects of E2 on cardiac function following T-H are mediated via ERbeta up-regulation of PGC-1alpha through Tfam-dependent pathway.
Hsieh
Ya-Ching
YC
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall, Rm. G094, Birmingham, Alabama 35294-0019, USA.
Choudhry
Mashkoor A
MA
Yu
Huang-Ping
HP
Shimizu
Tomoharu
T
Yang
Shaolong
S
Suzuki
Takao
T
Chen
Jianguo
J
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006470:Hemorrhage / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D050356:Lipid Metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009570:Nitriles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010636:Phenols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017695:Soft Tissue Injuries / Q000150:complications; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D018955:CD36 Antigens; D002316:Cardiotonic Agents; D047628:Estrogen Receptor alpha; D009570:Nitriles; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010636:Phenols; C501429:Ppargc1a protein, rat; D011422:Propionates; D011720:Pyrazoles; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D000255:Adenosine Triphosphate; D042964:Acyl-CoA Dehydrogenase; D003576:Electron Transport Complex IV