Abnormal Expression of Prolyl Oligopeptidase (POP) and Its Catalytic Products Ac-SDKP Contributes to the Ovarian Fibrosis Change in Polycystic Ovary Syndrome (PCOS) Mice

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Jul 29

PMID 37509566

Authors

Suo Han

Shimeng Wang

Xiang Fan

Mengchi Chen

Xiaojie Wang

Yingtong Huang

Hongdan Zhang

Yinyin Ma

Jing Wang

Chunping Zhang

Affiliations

Soon will be listed here.

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disorder and metabolic syndrome. Ovarian fibrosis pathological change in PCOS has gradually attracted people's attention. In this study, we constructed a PCOS mouse model through the use of dehydroepiandrosterone. Sirius red staining showed that the ovarian tissues in PCOS mice had obvious fibrosis. Prolyl oligopeptidase (POP) is a serine protease and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is its catalytic product. Studies show that abnormal expression and activity of POP and Ac-SDKP are closely related to tissue fibrosis. It was found that the expression of POP and Ac-SDKP was decreased in the ovaries of PCOS mice. Further studies showed that POP and Ac-SDKP promoted the expression of matrix metalloproteinases 2 (MMP-2) expression and decreased the expression of transforming growth factor beta 1 (TGF-β1) in granulosa cells. Hyperandrogenemia is a typical symptom of PCOS. We found that testosterone induced the low expression of POP and MMP2 and high expression of TGF-β1 in granulosa cells. POP overexpression and Ac-SDKP treatment inhibited the effect of testosterone on TGF-β1 and MMP2 in vitro and inhibited ovarian fibrosis in the PCOS mouse model. In conclusion, PCOS ovarian tissue showed obvious fibrosis. Low expression of POP and Ac-SDKP and changes in fibrotic factors contribute to the ovarian pathological fibrosis induced by androgen.

Citing Articles

LncPrep + 96kb inhibits ovarian fibrosis by upregulating prolyl oligopeptidase expression.

Zhang H, Wang J, Liu J, Fan X, Jia Y, Huang Y Mol Med Rep. 2025; 31(5).

PMID: 40017148 PMC: 11894593. DOI: 10.3892/mmr.2025.13478.

References

Amargant F, Manuel S, Tu Q, Parkes W, Rivas F, Zhou L . Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Aging Cell. 2020; 19(11):e13259. PMC: 7681059. DOI: 10.1111/acel.13259. View

Ohta N, Takahashi T, Mori T, Park M, Kawashima S, Takahashi K . Hormonal modulation of prolyl endopeptidase and dipeptidyl peptidase IV activities in the mouse uterus and ovary. Acta Endocrinol (Copenh). 1992; 127(3):262-6. DOI: 10.1530/acta.0.1270262. View

Woodruff T, Shea L . The role of the extracellular matrix in ovarian follicle development. Reprod Sci. 2008; 14(8 Suppl):6-10. PMC: 2648348. DOI: 10.1177/1933719107309818. View

Ahmed H, Umar M, Imran S, Javaid F, Syed S, Riaz R . TGF-β1 signaling can worsen NAFLD with liver fibrosis backdrop. Exp Mol Pathol. 2021; 124:104733. DOI: 10.1016/j.yexmp.2021.104733. View

Tenorio-Laranga J, Montoliu C, Urios A, Hernandez-Rabaza V, Ahabrach H, Garcia-Horsman J . The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients. J Neuroinflammation. 2015; 12:183. PMC: 4589196. DOI: 10.1186/s12974-015-0404-7. View

Jaseem Khan M, Ullah A, Basit S . Genetic Basis of Polycystic Ovary Syndrome (PCOS): Current Perspectives. Appl Clin Genet. 2020; 12:249-260. PMC: 6935309. DOI: 10.2147/TACG.S200341. View

Tal R, Seifer D, Shohat-Tal A, Grazi R, Malter H . Transforming growth factor-β1 and its receptor soluble endoglin are altered in polycystic ovary syndrome during controlled ovarian stimulation. Fertil Steril. 2013; 100(2):538-43. DOI: 10.1016/j.fertnstert.2013.04.022. View

Lo B, Archibong-Omon A, Ploutarchou P, Day A, Milner C, Williams S . Oocyte-specific ablation of N- and O-glycans alters cumulus cell signalling and extracellular matrix composition. Reprod Fertil Dev. 2018; 31(3):529-537. DOI: 10.1071/RD18209. View

Zhang X, Zhang C, Shen S, Xia Y, Yi L, Gao Q . Dehydroepiandrosterone induces ovarian and uterine hyperfibrosis in female rats. Hum Reprod. 2013; 28(11):3074-85. DOI: 10.1093/humrep/det341. View

10.

Kinnear H, Tomaszewski C, Chang A, Moravek M, Xu M, Padmanabhan V . The ovarian stroma as a new frontier. Reproduction. 2020; 160(3):R25-R39. PMC: 7453977. DOI: 10.1530/REP-19-0501. View

11.

Umehara T, Richards J, Shimada M . The stromal fibrosis in aging ovary. Aging (Albany NY). 2018; 10(1):9-10. PMC: 5811253. DOI: 10.18632/aging.101370. View

12.

Dunlop C, Anderson R . The regulation and assessment of follicular growth. Scand J Clin Lab Invest Suppl. 2014; 244:13-7. DOI: 10.3109/00365513.2014.936674. View

13.

Aflatounian A, Edwards M, Rodriguez Paris V, Bertoldo M, Desai R, Gilchrist R . Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model. J Endocrinol. 2020; 245(3):381-395. DOI: 10.1530/JOE-19-0530. View

14.

Tenorio-Laranga J, Peltonen I, Keskitalo S, Duran-Torres G, Natarajan R, Mannisto P . Alteration of prolyl oligopeptidase and activated α-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome. Biochem Pharmacol. 2013; 85(12):1783-94. DOI: 10.1016/j.bcp.2013.04.018. View

15.

Peng H, Carretero O, Brigstock D, Oja-Tebbe N, Rhaleb N . Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension. Hypertension. 2003; 42(6):1164-70. PMC: 6824434. DOI: 10.1161/01.HYP.0000100423.24330.96. View

16.

Wang D, Wang W, Liang Q, He X, Xia Y, Shen S . DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway. J Ovarian Res. 2018; 11(1):6. PMC: 5763573. DOI: 10.1186/s13048-017-0375-7. View

17.

Kumar N, Nakagawa P, Janic B, Romero C, Worou M, Monu S . The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase. Am J Physiol Renal Physiol. 2016; 310(10):F1026-34. PMC: 4889319. DOI: 10.1152/ajprenal.00562.2015. View

18.

Wang F, Chang H, Yi Y, Li H, Leung P . TGF-β1 promotes hyaluronan synthesis by upregulating hyaluronan synthase 2 expression in human granulosa-lutein cells. Cell Signal. 2019; 63:109392. DOI: 10.1016/j.cellsig.2019.109392. View

19.

Hrenak J, Paulis L, Simko F . N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP): Potential target molecule in research of heart, kidney and brain. Curr Pharm Des. 2015; 21(35):5135-43. DOI: 10.2174/1381612821666150909093927. View

20.

Szeltner Z, Polgar L . Structure, function and biological relevance of prolyl oligopeptidase. Curr Protein Pept Sci. 2008; 9(1):96-107. DOI: 10.2174/138920308783565723. View