Heat shock protein induction blocks hormone-sensitive steroidogenesis in rat luteal cells.
A variety of agents induce heat shock proteins (HSPs) in addition to heat shock. The heat shock response and its effects on luteal function have not been investigated, but provocatively, many of the agents known to induce HSPs impair progesterone synthesis in luteal cells. We therefore investigated whether HSP induction might influence luteal function. Rat luteal cells exposed to a commonly used heat shock paradigm (45 degrees C; 10 min) were shown to induce HSP of 70 kDa (HSP-70). Heat shock also caused a complete abrogation of LH-sensitive progesterone and 20 alpha-dihydroprogesterone secretion, and blocked steroidogenesis in response to 8-bromo-cAMP and forskolin. In contrast, heat shock had no effect on cAMP accumulation in response to LH or forskolin, or on basal progestin secretion. Heat shock inhibition of steroidogenesis was fully reversed by 22R-hydroxycholesterol (22-OH cholesterol), a cell- and mitochondria-permeant cholesterol analog. Inhibition of transcription with actinomycin D blocked HSP-70 induction and significantly reversed the inhibition of steroidogenesis by heat shock treatment. The antisteroidogenic response of heat shock was coincident with induction of HPSs and both events were transcription dependent. These findings provide strong evidence that HSP induction inhibits steroidogenesis. The mechanism of the antisteroidogenic action of HSP induction appears to be due to interference with translocation of cholesterol to mitochondrial cytochrome P450scc, a conclusion based on reversal of inhibition by 22-OH cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
Khanna
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A
Department of Obstetrics/Gynecology, Yale University, New Haven, CT 06520.
Aten
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RF
Behrman
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HR
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006728:Hormones / Q000494:pharmacology*; D006358:Hot Temperature; D006888:Hydroxycholesterols / Q000494:pharmacology; D008184:Luteal Cells / Q000187:drug effects / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000494:pharmacology; D011374:Progesterone / Q000096:biosynthesis*; D051381:Rats; D014158:Transcription, Genetic
D006360:Heat-Shock Proteins; D006728:Hormones; D006888:Hydroxycholesterols; C003585:22-hydroxycholesterol; D003609:Dactinomycin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D007986:Luteinizing Hormone; D000242:Cyclic AMP