Bresson Eva, Lacroix-Pépin Nicolas, Boucher-Kovalik Sofia, Chapdelaine Pierre, Fortier Michel A
Unité de Recherche en Ontogénie et Reproduction, Centre Hospitalier Universitaire de Québec, Centre de Recherche en Biologie de la Reproduction, Département d'Obstétrique et Gynécologie, Université Laval, Ste-Foy QC, Canada.
Front Pharmacol. 2012 May 25;3:98. doi: 10.3389/fphar.2012.00098. eCollection 2012.
Prostaglandins are important regulators of female reproductive functions to which aldose reductases exhibiting hydroxysteroid dehydrogenase activity also contribute. Our work on the regulation of reproductive function by prostaglandins (PGs), lead us to the discovery that AKR1B5 and later AKR1B1were highly efficient and physiologically relevant PGF synthases. PGE2 and PGF2α are the main prostanoids produced in the human endometrium and proper balance in their relative production is important for normal menstruation and optimal fertility. Recent evidence suggests that PGE2/EP2 and PGF2α/FP may constitute a functional dyad with physiological relevance comparable to the prostacyclin-thromboxane dyad in the vascular system. We have recently reported that AKR1B1 was expressed and modulated in association with PGF2α production in response to IL-1β in the human endometrium. In the present study, we show that the human AKR1B1 (gene ID: 231) also known as ALDR1 or ALR2 is a functional PGF2α synthase in different models of living cells and tissues. Using human endometrial cells, prostate, and vascular smooth muscle cells, cardiomyocytes and endothelial cells we demonstrate that IL-1β is able to up regulate COX-2 and AKR1B1 proteins as well as PGF2α production under normal glucose concentrations. We show that the promoter activity of AKR1B1 gene is increased by IL-1β particularly around the multiple stress response region containing two putative antioxidant response elements adjacent to TonE and AP1. We also show that AKR1B1 is able to regulate PGE2 production through PGF2α acting on its FP receptor and that aldose reductase inhibitors like alrestatin, Statil (ponalrestat), and EBPC exhibit distinct and characteristic inhibition of PGF2α production in different cell models. The PGF synthase activity of AKR1B1 represents a new and important target to regulate ischemic and inflammatory responses associated with several human pathologies.
前列腺素是女性生殖功能的重要调节因子，具有羟基类固醇脱氢酶活性的醛糖还原酶也参与其中。我们关于前列腺素（PGs）对生殖功能调节的研究，使我们发现AKR1B5以及后来的AKR1B1是高效且与生理相关的PGF合成酶。PGE2和PGF2α是人类子宫内膜产生的主要前列腺素，它们相对产量的适当平衡对于正常月经和最佳生育能力很重要。最近的证据表明，PGE2/EP2和PGF2α/FP可能构成一个功能二元组，其生理相关性与血管系统中的前列环素 - 血栓素二元组相当。我们最近报道，在人类子宫内膜中，AKR1B1的表达和调节与PGF2α的产生有关，以响应IL - 1β。在本研究中，我们表明人类AKR1B1（基因ID：231），也称为ALDR1或ALR2，在不同的活细胞和组织模型中是一种功能性PGF2α合成酶。使用人类子宫内膜细胞、前列腺、血管平滑肌细胞、心肌细胞和内皮细胞，我们证明在正常葡萄糖浓度下，IL - 1β能够上调COX - 2和AKR1B1蛋白以及PGF2α的产生。我们表明，IL - 1β可增加AKR1B1基因的启动子活性，特别是在包含两个与TonE和AP1相邻的假定抗氧化反应元件的多重应激反应区域周围。我们还表明，AKR1B1能够通过PGF2α作用于其FP受体来调节PGE2的产生，并且醛糖还原酶抑制剂如阿雷司他、司他立（泊那司他）和EBPC在不同细胞模型中对PGF2α的产生表现出独特且具有特征性的抑制作用。AKR1B1的PGF合成酶活性代表了一个新的重要靶点，可用于调节与多种人类疾病相关的缺血和炎症反应。
