Distribution and function of 3′,5′-Cyclic-AMP phosphodiesterases in the human ovary

Petersen, Tonny Studsgaard; Kristensen, Stine Gry; Jeppesen, Janni Vikkelsø; Grøndahl, Marie Louise; Wissing, Marie Louise Muff; Macklon, Kirsten Tryde; Andersen, Claus Yding

doi:10.1016/j.mce.2015.01.004

Cited by 23 publications

(27 citation statements)

References 67 publications

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“…We saw a relative low expression of Pde4d compared to the enzymatic activity of PDE4. Recently, similar results have been reported in human GCs (Petersen et al 2015). This could be due to a rapid turnover of the mRNA as seen with other transcripts involved in signalling (Schwanhausser et al 2011).…”

Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 81%

“…Low level of Pde8b was seen in contrast to that observed in bovine ovaries (Sasseville et al 2009) and in humans (Markholt et al 2012, Petersen et al 2015. Instead, Pde8a appeared to be the major subtype present, especially in the CL.…”

Section: Phosphodiesterases In the Rat Ovarymentioning

confidence: 67%

“…In the rodent ovary, PDE4D and PDE3 are known to exert important roles in regulation of oocyte maturation and ovulation (Tsafriri et al 1996, Park et al 2003, Conti et al 2012. In addition, the presence of PDE8 has been reported in the bovine and human ovary (Sasseville et al 2009, Petersen et al 2015 but has not been studied in rodents.…”

Section: Introductionmentioning

confidence: 99%

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Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15-26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation. Reproduction (2015) 150 11-20

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Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 81%

Section: Phosphodiesterases In the Rat Ovarymentioning

confidence: 67%

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Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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“…Several isoforms of PDE are detected in cultured granulosa cells, such as PDE4, PDE7, and PDE8. While inhibition of PDE7 and PDE8 is responsible for alterations in basal hormone secretion, PDE4 activity is involved in the forskolin‐stimulated progesterone production . As T‐2 toxin inhibits the hormone‐supported progesterone production, it is reasonable to suggest that PDE4 could be the main target of T‐2 toxin's action.…”

Section: Discussionmentioning

confidence: 99%

“…19 Our results further reveal that T-2 toxin-induced suppression of cAMP production in the FSH-stimulated cells is most likely mediated by acti- is involved in the forskolin-stimulated progesterone production. 43 As T-2 toxin inhibits the hormone-supported progesterone production, it is reasonable to suggest that PDE4 could be the main target of T-2 toxin's action. The exact PDE isoform affected and the mechanism by which T-2 toxin alters these enzymes remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

T‐2 toxin downregulates LHCGR expression, steroidogenesis, and cAMP level in human cumulus granulosa cells

Pogrmić-Majkić

Nenadov

Stanić

et al. 2019

Environmental Toxicology

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Our goals were to investigate whether environmentally relevant doses of T‐2 toxin can affect human ovarian granulosa cells' function and to reveal the potential mechanism of T‐2 toxin's action. Results showed that T‐2 toxin strongly attenuated luteinizing hormone/choriogonadotropin receptor (LHCGR) mRNA expression in follicle‐stimulating hormone (FSH)‐stimulated human cumulus granulosa cells. Addition of human chorionic gonadotropin was not able to elicit maximal response of ovulatory genes amphiregulin, epiregulin, and progesterone receptor. T‐2 toxin reduced mRNA levels of CYP19A1 and steroidogenic acute regulatory protein (STAR) and lowered FSH‐stimulated estradiol and progesterone production. Mechanistic experiments demonstrated that T‐2 toxin decreased FSH‐stimulated cyclic adenosine monophosphate (cAMP) production. Addition of total PDE inhibitor 3‐isobutyl‐1‐methylxanthine prevented T‐2 toxin's action on LHCGR, STAR, and CYP19A1 mRNA expression in FSH‐stimulated human cumulus granulosa cells. Furthermore, T‐2 toxin partially decreased 8‐bromoadenosine 3′5′‐cyclic monophosphate (8‐Br‐cAMP)‐stimulated LHCGR and STAR, but did not affect 8‐Br‐cAMP‐stimulated CYP19A1 mRNA expression in human cumulus granulosa cells. Overall, our data indicate that environmentally relevant dose of T‐2 toxin decreases steroidogenesis and ovulatory potency in human cumulus granulosa cells probably through activation of PDE, thus posing a significant risk for female fertility.

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PDE4 inhibitor Roflumilast modulates inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA‐induced granulosa cell apoptosis in vitro

Yao

Wang

Liu

et al. 2023

Drug Development Research

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This study was implemented to address the role of Roflumilast in polycystic ovary syndrome (PCOS) as well as to discuss its reaction mechanism in vivo and in vitro. In vivo, mice were administrated with 6 mg dehydroepiandrosterone (DHEA) per 100 g body weight and fed with 60% high fat diet to induce PCOS. The expression of phosphodiesterases 4 (PDE4) was assessed with RT-qPCR. The ovary pathology was observed by hematoxylin and eosin staining and follicles were counted. Enzymelinked immunosorbent assay was adopted for the estimation of progesterone, testosterone and inflammatory factors and lipid accumulation was observed by Oil Red O staining. With the application of reverse transcription-quantitative PCR (RT-qPCR) and western blot, the messenger RNA (mRNA) and protein expressions of low-density lipoprotein receptor (LDLR) was resolved. In vitro, Cell counting kit-8 and flow cytometry analysis were applied for the assessment of cell proliferation and apoptosis. The proliferation-and apoptosis-related proteins were appraised with western blot. Additionally, the expressions of PDE-4 at both mRNA and protein levels were tested with RT-qPCR and western blot. Here, it was discovered that PDE4 was greatly elevated in PCOS mice and DHEA-induced ovarian granulosa cells (KGN). In PCOS mice, PDE4 was negative correlated with progesterone and had positive correlation with testosterone. Roflumilast could enhanced progesterone expression, increased the number of primary follicles, preantral follicles and antral follicles but reduced testosterone and decreased the number of cystic follicles in PCOS mice. It was also testified that Roflumilast could inhibit the release of inflammatory factors and lipid accumulation in PCOS mice. Besides, the proliferation of DHEA-induced KGN cells was enhanced while the apoptosis was declined by Roflumilast, accompanied by elevated contents of PCNA, Ki67 and antiapoptotic protein Bcl-2. Collectively, Roflumilast inhibited inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis.

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Distribution and function of 3′,5′-Cyclic-AMP phosphodiesterases in the human ovary

Cited by 23 publications

References 67 publications

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

T‐2 toxin downregulates LHCGR expression, steroidogenesis, and cAMP level in human cumulus granulosa cells

PDE4 inhibitor Roflumilast modulates inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA‐induced granulosa cell apoptosis in vitro

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