The peroxisome proliferator-activated receptor γ ligand troglitazone induces apoptosis and p53 in rat granulosa cells

PPAR gamma is expressed in both the rodent and human ovary, but the endogenous activation state of PPAR gamma in the ovary and its normal role in ovarian function remain unclear. Here, we investigated mRNA and protein expression as well as DNA-binding activity of PPAR gamma during follicle growth and luteinization in the immature, gonadotropin-primed rat model. Gel shift analysis demonstrated binding of ovarian PPAR to a consensus peroxisome proliferator response element (PPRE) that was supershifted with an antibody specific for PPAR gamma, but not with antibodies specific for PPAR alpha or beta/delta. PPAR gamma expression and DNA-binding activity was highest 0-12 h post-PMSG, but declined during later stages of follicle growth (24-36 h post-PMSG). Administration of hCG induced a decline in PPAR gamma mRNA, protein, and DNA-binding activity beginning at 4 h. Treatment of preovulatory granulosa cells with the PPAR gamma ligand troglitazone (1-10 mu M) in vitro decreased cell viability, increased sub-G I apoptosis, and reduced DNA synthesis. Troglitazone induced p53 protein expression and decreased bcl-2 mRNA, suggesting possible mechanisms for troglitazone-induced apoptosis. These data indicate that PPAR gamma is in the ovary is capable of binding DNA in the absence of pharmacological activation and provide evidence for a possible physiologic role for this receptor in regulating granulosa cell survival. (c) 2005 Elsevier Ireland Ltd. All rights reserved.