Inhibition of cardiac PGC‐1alpha expression abolishes estrogen receptor (ER) beta agonist‐mediated cardioprotection following trauma‐hemorrhage (T‐H)

Abstract

PGC-1α[peroxisome proliferator-activated receptor (PPARγ) coactivator-1α ], known for its role in mitochondrial (Mt) function,regulates a number of genes required for Mt fatty acid metabolism and ATP production. More specifically, PGC-1αactivates transcription factors such as PPARαand Mt transcription factor A (Tfam), which regulates the proteins of fatty acid and ATP metabolism (i.e., FAT/CD36 andMtDNA-encoded COX I). Recent studies indicate that the salutary effects of E2 on cardiac function following T-H are mediated via ERβ . Accordingly, we hypothesized that ERβ-mediated cardioprotection is induced via upregulation of PGC-1αthrough PPARαor Tfam-dependent pathway. To examine this, male rats underwent T-H (BP 40 mmHg for 90 min) followed by resuscitation. At the middle of resuscitation, rats received either ERαagonist propylpyrazole-triol (PPT), ERβagonist diarylpropionitrile (DPN), E2, or vehicle. Another group was treated with antisense PGC-1αoligonucleotides prior to administration of DPN.E2 or DPN treatment attenuated the decrease in cardiac Mt ATP, abrogated the T-H-induced lipid accumulation, and normalized PGC-1α, PPARα, Tfam, FAT/CD36, and COX I at 2 h after T-H (p<0.05 vs. vehicle). In contrast, PPT did not abrogate lipid accumulation. Moreover, Mt ATP levels remained significantly lower than those observed in DPN- or E2-treated rats. Prior administration of antisense PGC-1αoligonucleotide prevented DPN-mediated cardioprotection and the increase in ATP and Tfam levels but not in PPARαlevels following T-H. These findings indicate that the salutary effects of E2 on cardiac function following T-H are mediated via ERβupregulation of PGC-1αthrough Tfam-dependent pathway (NIH grant R37 GM39519).