Upregulation of mitochondrial respiratory complex IV by estrogen receptor-β is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma–hemorrhage

Abstract

Our recent study showed that estrogen receptor (ER) β plays a major role in mediating the salutary effects of 17β-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 ERβ-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 ∼ 90 min, then resuscitation). During resuscitation, rats received either ERα agonist propylpyrazole triol (PPT; 5 μg/kg), ERβ agonist diarylpropionitrile (DPN; 5 μg/kg), E2 (50 μg/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 ERβ expression and increased mitochondrial ERβ 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 ERβ-mediated cardioprotection following T–H appears to be mediated via mitochondrial ERβ-dependent MRC-IV activity and inhibition of mitochondrial apoptotic signaling pathways.