Upregulation of mitochondrial respiratory complex IV by estrogen receptor-beta is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma-hemorrhage.
Our recent study showed that estrogen receptor (ER) beta plays a major role in mediating the salutary effects of 17beta-estradiol (E2) on cardiac function following trauma-hemorrhage (T-H). E2 is known to regulate mitochondrial DNA (mtDNA)-encoded genes including the mitochondrial respiratory complex (MRC) proteins. Depressed MRC activity has been reported to promote the release of cytochrome c from mitochondria and induce apoptosis. We hypothesized that E2 and ERbeta-mediated cardioprotection following T-H is dependent on mtDNA transcription encoding for MRC activity. To test this, male rats underwent T-H (mean BP 40 mm Hg approximately 90 min, then resuscitation). During resuscitation, rats received either ERalpha agonist propylpyrazole triol (PPT; 5 microg/kg), ERbeta agonist diarylpropionitrile (DPN; 5 microg/kg), E2 (50 microg/kg), or vehicle (10% DMSO). Another group of rats received mitochondrial respiratory complex-IV (MRC-IV) inhibitor sodium cyanide (SCN; 6 mg/kg) with or without DPN. The results indicated that 24 h after T-H, cardiac functions were depressed in the vehicle-treated but were normal in the DPN-treated rats. Moreover, E2 or DPN treatment after T-H normalized cardiac mitochondrial ERbeta expression and increased mitochondrial ERbeta DNA-binding activity. This was accompanied by an increase in MRC-IV gene expressions and activity, while MRC-I gene expression remained unchanged. Inhibition of MRC-IV in DPN-treated T-H rats by SCN abolished the DPN-mediated cardioprotection, ATP production, mitochondrial cytochrome c release, caspase-3 cleavage, and apoptosis. Thus, E2 and ERbeta-mediated cardioprotection following T-H appears to be mediated via mitochondrial ERbeta-dependent MRC-IV activity and inhibition of mitochondrial apoptotic signaling pathways.
Hsieh
Ya-Ching
YC
Center for Surgical Research, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Yu
Huang-Ping
HP
Suzuki
Takao
T
Choudhry
Mashkoor A
MA
Schwacha
Martin G
MG
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006470:Hemorrhage / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000473:pathology*; D015854:Up-Regulation
D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D053148:Caspase 3