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Submitted on October 15, 2004
Accepted on December 3, 2004
suppresses 11
-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells
Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Children's Health Research Institute & Lawson Health Research Institute, Departments of Obstetrics & Gynaecology and Physiology & Pharmacology, University of Western Ontario, 800 Commissioners Rd. E., London, Ontario, Canada N6A 4G5
* To whom correspondence should be addressed. E-mail: kyang{at}uwo.ca.
Accumulating evidence suggests that the human placental enzyme 11
-hydroxysteroid dehydrogenase type 2 (11-HSD2) plays a key role in fetal development by controlling fetal exposure to maternal glucocorticoids. Recently, the nuclear receptor PPAR
has been found to be the most abundantly expressed PPAR subtype in the human placenta, but its function in this organ is unknown. Given that PPAR null mice exhibited placental defects and consequent intrauterine growth restriction, the present study was undertaken to examine the hypothesis that PPAR regulates human placental function in part by targeting 11-HSD2. Using cultured human trophoblast cells as a model system, we demonstrated that (a) the putative PPAR agonist carbaprostacyclin (cPGI2) reduced 11-HSD2 activity as well as 11-HSD2 expression at both protein and mRNA levels; (b) GW610742 (a selective PPAR agonist) mimicked the effect of cPGI2, while indomethacin (a known ligand for PPAR
and PPAR
) had no effect; (c) the cPGI2-induced down-regulation of 11-HSD2 mRNA did not require de novo protein synthesis; (d) cPGI2 suppressed HSD11B2 promoter activity but did not alter the half-life of 11-HSD2 mRNA; and (e) the inhibitory effect of cPGI2 on HSD11B2 promoter activity was abrogated in trophoblast cells co-transfected with a dominant-negative PPAR mutant. Taken together, these findings suggest that activation of PPAR down-regulates HSD11B2 gene expression in human trophoblast cells, and that this effect is mediated primarily at the transcriptional level. Thus, the present study reveals 11-HSD2 as an additional target for PPAR and identifies a molecular mechanism by which this nuclear receptor may regulate human placental function.
-HSD2 •
human placenta •
trophoblast cells •
PPAR •
qRT-PCR
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