A Novel Pathway Involving Progesterone Receptor, 12/ 15-Lipoxygenase-derived Eicosanoids, and Peroxisome Proliferator-activated Receptor γ Regulates Implantation in Mice

Quanxi Li, Yong Pil Cheon, Athilaxmi Kannan, Sreenath Shanker, Indrani C. Bagchi, Milan K. Bagchi

Research output: Contribution to journalArticle

Abstract

The 12/15-lipoxygenases (12/15-LOX) catalyze the stereo-specific oxygenation of arachidonic and linoleic acids into a complex series of signaling molecules, including the hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs). Our previous studies, using high density oligonucleotide microarrays, suggested a novel link between progesterone receptor (PR) signaling and 12/15-LOX-mediated fatty acid metabolism in preimplantation mouse uterus. In this paper, using PR knockout mice, we established that the transcripts encoding leukocyte-12/15-LOX (L-12/15-LOX) and epidermal-12/15-LOX (E-12/15-LOX) are indeed downstream targets of regulation by PR in the uterine surface epithelium. Maximal induction of both L- and E-12/15-LOX on the day of implantation resulted in a marked increase in the uterine levels of the eicosanoids, 12-HETE, 15-HETE, and 13-HODE. Mice with null mutation in L-12/15-LOX had significantly reduced uterine levels of arachidonic acid metabolites and exhibited a partial impairment in implantation. Complete blockade of uterine 12/15-LOX activity by a specific inhibitor led to greater than 80% reduction in a number of implantation sites relative to untreated controls. Cell-based assays indicated that 12-HETE, 15-HETE, and 13-HODE function as activating ligands of peroxisome proliferator-activated receptor γ (PPARγ), suggesting that this nuclear receptor could be a downstream target of 12/15-LOX-derived metabolites in the preimplantation uterus. Consistent with this hypothesis, administration of rosiglitazone, a potent PPARγ-selective agonist, efficiently reversed inhibition of implantation by the 12/15-LOX-specific inhibitor. Rosiglitazone also induced a number of potential target genes of 12/15-LOX-derived metabolites in the pregnant uterus, indicating their regulation by PPARγ. Collectively, our results uncovered a novel signaling pathway in which progesterone-induced synthesis of the 12/15-LOX-derived lipid mediators activates PPARγ and its downstream gene networks, which in turn function as critical regulators of implantation in the mouse.

Original languageEnglish (US)
Pages (from-to)11570-11581
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number12
DOIs
StatePublished - Mar 19 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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