文章基本信息

标题：Prostaglandin dehydrogenase is a target for successful induction of cervical ripening
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作者：Annavarapu Hari Kishore ; Hanquan Liang ; Mohammed Kanchwala 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：31
页码：E6427-E6436
DOI：10.1073/pnas.1704945114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E₂ or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE₂ uses cell-specific EP2 receptor-mediated increases in Ca²⁺ to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE₂ or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE₂ or metabolism-resistant dimethyl-PGE₂ resulted in preterm cervical ripening and delivery in mice. The ability of PGE₂ to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of 15-PGDH elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for ( i ) the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE₂-mediated cervical ripening or ( ii ) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.
关键词：prostaglandin E₂ ; cervical shortening ; preterm labor ; labor induction ; HDAC4