Progesterone-receptor antagonists and statins decrease de novo cholesterol synthesis and increase apoptosis in rat and human periovulatory granulosa cells in vitro.
Progesterone-receptor (PR) stimulation promotes survival in rat and human periovulatory granulosa cells. To investigate the mechanisms involved, periovulatory rat granulosa cells were incubated in vitro with or without the PR-antagonist Org 31710. Org 31710 caused the expected increase in apoptosis, and expression profiling using cDNA microarray analysis revealed regulation of several groups of genes with functional and/or metabolic connections. This regulation included decreased expression of genes involved in follicular rupture, increased stress responses, decreased angiogenesis, and decreased cholesterol synthesis. A decreased cholesterol synthesis was verified in experiments with both rat and human periovulatory granulosa cells treated with the PR-antagonists Org 31710 or RU 486 by measuring incorporation of [14C]acetate into cholesterol, cholesterol ester, and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory rat granulosa cells using 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (lovastatin, mevastatin, or simvastatin) increased apoptosis, measured as DNA fragmentation and caspase-3/7 activity. The increase in apoptosis caused by simvastatin was reversed by addition of the cholesterol synthesis-intermediary mevalonic acid. These results show that PR antagonists reduce cholesterol synthesis in periovulatory granulosa cells and that cholesterol synthesis is important for granulosa cell survival.
Rung
Emilia
E
Department of Physiology and Pharmacology, Göteborg, Sweden.
Friberg
P Anders
PA
Shao
Ruijin
R
Larsson
D G Joakim
DG
Nielsen
Eva Ch
ECh
Svensson
Per-Arne
PA
Carlsson
Björn
B
Carlsson
Lena M S
LM
Billig
Håkan
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000096:biosynthesis*; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D015735:Mifepristone / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010060:Ovulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004963:Estrenes; D005663:Furans; D006727:Hormone Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011980:Receptors, Progesterone; C076196:Org 31710; D015735:Mifepristone; D002784:Cholesterol