Upregulation of mitochondrial respiratory complex IV by estrogen receptor-β 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 17 beta-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 ER beta-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 similar to 90 min, then resuscitation). During resuscitation, rats received either ER alpha agonist propylpyrazole triol (PPT; 5 mu g/kg), ER agonist diarylpropionitrile (DPN; 5 mu g/kg), E2 (50 mu g/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 ER beta expression and increased mitochondrial ER beta 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 ER beta-mediated cardioprotection following T-H appears to be mediated via mitochondrial ER beta-dependent MRC-IV activity and inhibition of mitochondrial apoptotic signaling pathways. (c) 2006 Elsevier Inc. All rights reserved.