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Progesterone-receptor antagonists and statins decrease de novo cholesterol synthesis and increase apoptosis in rat and human periovulatory granulosa cells in vitro

Artikel i vetenskaplig tidskrift
Författare Emilia Rung
P. Anders Friberg
Linus Ruijin Shao
D. G. Joakim Larsson
Eva Ch. Nielsen
Per-Arne Svensson
Björn Carlsson
Lena M S Carlsson
Håkan Billig
Publicerad i Biology of reproduction
Volym 72
Nummer/häfte 3
Sidor 538-45
ISSN 0006-3363 (Print)
Publiceringsår 2005
Publicerad vid Institutionen för invärtesmedicin, Avdelningen för kroppssammansättning och metabolism
Institutionen för fysiologi och farmakologi, Avdelningen för fysiologi
Sidor 538-45
Språk en
Länkar dx.doi.org/10.1095/biolreprod.104.0...
Ämnesord Animals, Apoptosis/drug effects/*physiology, Cell Survival/physiology, Cholesterol/*biosynthesis, Estrenes/pharmacology, Female, Furans/pharmacology, Gene Expression Profiling, Gene Expression Regulation, Granulosa Cells/drug effects/*metabolism, Hormone Antagonists/pharmacology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Mifepristone/pharmacology, Oligonucleotide Array Sequence Analysis, Ovulation/*physiology, Rats, Rats, Sprague-Dawley, Receptors, Progesterone/antagonists & inhibitors/*metabolism, Signal Transduction/physiology
Ämneskategorier Medicin och Hälsovetenskap, Fysiologi

Sammanfattning

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.

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