School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, 2308, Australia.
Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
Reprod Sci. 2024 Jan;31(1):150-161. doi: 10.1007/s43032-023-01333-6. Epub 2023 Aug 30.
Metabolic inactivation of progesterone within uterine myocytes by 20α-hydroxysteroid dehydrogenase (20α-HSD) has been postulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20α-HSD is encoded by the gene AKR1C1. Myometrial AKR1C1 mRNA abundance has been reported to increase significantly during labor at term. In spontaneous preterm labor, however, we previously found no increase in AKR1C1 mRNA level in the myometrium except for preterm labor associated with clinical chorioamnionitis. This suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. In this study, we have determined the effects of various treatments of therapeutic relevance on AKR1C1 expression in pregnant human myometrium in an ex vivo culture system. AKR1C1 expression increased spontaneously during 48 h culture (p < 0.0001), consistent with the myometrium transitioning to a labor-like phenotype ex vivo, as reported previously. Serum supplementation, prostaglandin F, phorbol myristate acetate, and mechanical stretch had no effect on the culture-induced increase, whereas progesterone (p = 0.0058) and cAMP (p = 0.0202) further upregulated AKR1C1 expression. In contrast, culture-induced upregulation of AKR1C1 expression was dose-dependently repressed by three histone/protein deacetylase inhibitors: trichostatin A at 5 (p = 0.0172) and 25 µM (p = 0.0115); suberoylanilide hydroxamic acid at 0.5 (p = 0.0070), 1 (p = 0.0045), 2.5 (p = 0.0181), 5 (p = 0.0066) and 25 µM (p = 0.0014); and suberoyl bis-hydroxamic acid at 5 (p = 0.0480) and 25 µM (p = 0.0238). We propose the inhibition of histone/protein deacetylation helps to maintain the anti-inflammatory, pro-quiescence signaling of progesterone in pregnant human myometrium by blocking its metabolic inactivation. Histone deacetylase inhibitors may represent a class of agents that preserve or restore the progesterone sensitivity of the pregnant uterus.
子宫平滑肌细胞内的孕激素 20α-羟化酶（20α-HSD）的代谢失活被认为是足月时孕激素功能丧失的一种机制。在人类中，20α-HSD 由 AKR1C1 基因编码。据报道，足月分娩时子宫肌层的 AKR1C1 mRNA 丰度显著增加。然而，在自发性早产中，我们之前发现除了与临床绒毛膜羊膜炎相关的早产外，子宫肌层中 AKR1C1 mRNA 水平没有增加。这表明，增加的 20α-HSD 活性是炎症驱动早产中孕激素丧失的一种机制。在这项研究中，我们在离体培养系统中确定了与治疗相关的各种处理对妊娠人子宫肌层中 AKR1C1 表达的影响。AKR1C1 的表达在 48 小时培养过程中自发增加（p<0.0001），这与先前报道的子宫肌层在离体状态下向分娩样表型的转变一致。血清补充、前列腺素 F、佛波醇十四酸酯和机械拉伸对培养诱导的增加没有影响，而孕激素（p=0.0058）和 cAMP（p=0.0202）进一步上调了 AKR1C1 的表达。相比之下，三种组蛋白/蛋白去乙酰化酶抑制剂：曲古抑菌素 A 在 5（p=0.0172）和 25μM（p=0.0115）、琥珀酰亚胺基羟肟酸在 0.5（p=0.0070）、1（p=0.0045）、2.5（p=0.0181）、5（p=0.0066）和 25μM（p=0.0014）以及琥珀酰双羟肟酸在 5（p=0.0480）和 25μM（p=0.0238）浓度依赖性地抑制了培养诱导的 AKR1C1 表达上调。我们提出，抑制组蛋白/蛋白去乙酰化有助于通过阻断其代谢失活来维持孕激素在妊娠人子宫肌层中的抗炎、促静止信号。组蛋白去乙酰化酶抑制剂可能代表一类既能维持又能恢复妊娠子宫对孕激素敏感性的药物。
