Inhibition of cardiac PGC-1alpha expression abolishes ERbeta agonist-mediated cardioprotection following trauma-hemorrhage.

Abstract

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.

• Authors: Ya-Ching Hsieh, Mashkoor A Choudhry, Huang-Ping Yu, Tomoharu Shimizu, Shaolong Yang, Takao Suzuki, Jianguo Chen, Kirby I Bland, Irshad H Chaudry
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 20 Issue 8 Pg. 1109-17 (Jun 2006) ISSN: 1530-6860 [Electronic] United States
• PMID: 16770010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2,3-bis(4-hydroxyphenyl)-propionitrile
• CD36 Antigens
• Cardiotonic Agents
• Estrogen Receptor alpha
• Nitriles
• PPAR alpha
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phenols
• Ppargc1a protein, rat
• Propionates
• Pyrazoles
• RNA-Binding Proteins
• Tfam protein, rat
• Transcription Factors
• 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
• Estradiol
• Adenosine Triphosphate
• Acyl-CoA Dehydrogenase
• Electron Transport Complex IV

Topics

• Acyl-CoA Dehydrogenase (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• CD36 Antigens (metabolism)
• Cardiotonic Agents (antagonists & inhibitors, pharmacology)
• Electron Transport Complex IV (metabolism)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (agonists)
• Heart (drug effects, physiopathology)
• Hemorrhage (complications, metabolism, physiopathology)
• Lipid Metabolism
• Male
• Mitochondria, Heart (metabolism)
• Myocardium (metabolism)
• Nitriles (antagonists & inhibitors, pharmacology)
• PPAR alpha (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phenols (antagonists & inhibitors, pharmacology)
• Propionates (antagonists & inhibitors, pharmacology)
• Pyrazoles (antagonists & inhibitors, pharmacology)
• RNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Soft Tissue Injuries (complications)
• Transcription Factors (antagonists & inhibitors, metabolism)