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PDCD4 deficiency improved 4-vinylcyclohexene dioxide-induced mouse premature ovarian insufficiency
Jie Zhang1, Mengzhen Qin2, Chunyu Kao3
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Research Question:
What role does programmed cell death 4 (PDCD4) play in premature ovarian insufficiency (POI)?
Design:
A PDCD4 gene knockout (PDCD4-/-) mouse model was constructed, a POI mouse model was established similar to human POI with 4-vinylcyclohexene dioxide (VCD), a PDCD4-overexpressed adenovirus was designed and the regulatory role in POI in vitro and in vivo was investigated.
Results:
PDCD4 expression was significantly increased in the ovarian granulosa cells of patients with POI (P ≤ 0.002 protein and mRNA) and mice with VCD-induced POI (P < 0.001 protein expression in both mouse ovaries and granulosa cells). In POI-induced mice model, PDCD4 knockouts significantly increased anti-Müllerian hormone, oestrodiol and numbers of developing follicles, and the PI3K-AKT-Bcl2/Bax signalling pathway is involved in it.
Conclusion:
The expression and regulation of PDCD4 significantly affects the POI pathology in a mouse model. This effect is closely related to the regulation of Bcl2/Bax and the activation of the PI3K-AKT signalling pathway.
Insights
Programmed cell death 4 (PDCD4) is upregulated in premature ovarian insufficiency (POI). Reducing PDCD4 in mice improved ovarian function by influencing the PI3K-AKT-Bcl2/Bax pathway, suggesting a therapeutic target for POI.
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
- Cell Death Mechanisms
Background:
- Premature ovarian insufficiency (POI) is a debilitating condition affecting women of reproductive age.
- The molecular mechanisms underlying POI pathogenesis remain incompletely understood.
- Programmed cell death 4 (PDCD4) is a known tumor suppressor and regulator of apoptosis.
Purpose of the Study:
- To investigate the role of PDCD4 in the development and progression of premature ovarian insufficiency (POI).
- To explore the potential of targeting PDCD4 for therapeutic intervention in POI.
Main Methods:
- Generation of PDCD4 gene knockout (PDCD4-/-) and POI mouse models using 4-vinylcyclohexene dioxide (VCD).
- Construction of PDCD4-overexpressed adenovirus for in vitro and in vivo studies.
- Quantification of PDCD4 expression in human and mouse ovarian granulosa cells.
- Assessment of ovarian function markers (anti-Müllerian hormone, estradiol, follicle count) and signaling pathways (PI3K-AKT-Bcl2/Bax).
Main Results:
- PDCD4 expression was significantly elevated in ovarian granulosa cells of both human POI patients and VCD-induced POI mice.
- PDCD4 knockout in POI mice led to significant increases in anti-Müllerian hormone, estradiol, and developing follicles.
- The PI3K-AKT signaling pathway and the Bcl2/Bax ratio were identified as key mediators of PDCD4's effect on POI.
Conclusions:
- PDCD4 expression and regulation play a critical role in POI pathology.
- Modulating PDCD4 levels impacts ovarian function and follicle development.
- Targeting the PI3K-AKT-Bcl2/Bax pathway in conjunction with PDCD4 offers a potential therapeutic strategy for POI.
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