title: Altered gene expression profile in ovarian follicle in rats treated with indomethacin and RU486.
abstract: It is well-known that indomethacin (the cyclooxygenase 1 & 2 inhibitor) and RU486 (or mifepristone, the progesterone receptor antagonist) block follicular rupture in rats. To characterize genetic alterations in unruptured follicles, gene expression profiles in ovarian follicle were analyzed in indomethacin- and RU486-treated female Sprague-Dawley rats. Ovaries are collected at 22:00 on the proestrus day and 10:00 on the following estrus day after a single dose of indomethacin and RU486. Histopathologically, changes depicting responses to LH surge were observed in ovaries, uteri and vagina. Total RNA was extracted from pre-ovulatory follicles or unruptured follicles collected by laser microdissection and analyzed by Genechip(®). Among genes showing statistically significant changes compared to control groups, following changes were considered relevant to induction of unruptured follicles. In indomethacin-treated rats, Wnt4 was down-regulated, suggesting effect on tissue integrity and steroid genesis. In RU486-treated rats, Adamts1, Adamts9, Edn2, Ednra, Lyve1, Plat, and Pparg were down-regulated. These changes suggest effects on proteolysis for extra cellular matrix or surrounding tissue (Adamts1 & 9, and Plat), constriction of smooth muscle surrounding follicles (Edn2, Ednra, and Pparg), follicular fluid (Lyve1), and angiogenesis (Pparg). Down-regulation of angiogenesis related genes (Angpt2, Hmox1, and Vegfa) was observed in both treatment groups. Here, we clarify genetic alterations induced by the inhibition of cyclooxygenase or progesterone receptor.
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma Inc.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Tsubota
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanki
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.forename: Shunji
authors.initials: S
authors.lastname: Nakatsuji
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oishi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D006080:Ovarian Follicle; D059748:Proteolysis / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D006727:Hormone Antagonists; D011980:Receptors, Progesterone; D015735:Mifepristone; D007213:Indomethacin