Park Sun-Ji, Kim Jung-Hak, Kim Tae-Shin, Lee Sang-Rae, Park Jeen-Woo, Lee Seunghoon, Kim Jin-Man, Lee Dong-Seok
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; Renal Division, School of medicine, Washington University in St Louis, MO, USA.
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
Free Radic Biol Med. 2017 Jul;108:44-55. doi: 10.1016/j.freeradbiomed.2017.03.013. Epub 2017 Mar 18.
Luteal regression is a natural and necessary event to regulate the reproductive process in all mammals. Prostaglandin F2α (PGF2α) is the main factor that causes functional and structural regression of the corpus luteum (CL). It is well known that PGF2α-mediated ROS generation is closely involved in luteal regression. Peroxiredoxin 2 (Prx2) as an antioxidant enzyme plays a protective role against oxidative stress-induced cell death. However, the effect of Prx2 on PGF2α-induced luteal regression has not been reported. Here, we investigated the role of Prx2 in functional and structural CL regression induced by PGF2α-mediated ROS using Prx2-deficient (-/-) mice. We found that PGF2α-induced ROS generation was significantly higher in Prx2-/- MEF cells compared with that in wild-type (WT) cells, which induced apoptosis by activating JNK-mediated apoptotic signaling pathway. Also, PGF2α treatment in the CL derived from Prx2-/- mice promoted the reduction of steroidogenic enzyme expression and the activation of JNK and caspase3. Compared to WT mice, serum progesterone levels and luteal expression of steroidogenic enzymes decreased more rapidly whereas JNK and caspase3 activations were significantly increased in Prx2-/- mice injected with PGF2α. However, the impaired steroidogenesis and PGF2α-induced JNK-dependent apoptosis were rescued by the addition of the antioxidant N-acetyl-L-cysteine (NAC). This is the first study to demonstrate that Prx2 deficiency ultimately accelerated the PGF2α-induced luteal regression through activation of the ROS-dependent JNK pathway. These findings suggest that Prx2 plays a crucial role in preventing accelerated luteal regression via inhibition of the ROS/JNK pathway.
黄体退化是调节所有哺乳动物生殖过程的自然且必要的事件。前列腺素F2α（PGF2α）是导致黄体（CL）功能和结构退化的主要因素。众所周知，PGF2α介导的活性氧（ROS）生成与黄体退化密切相关。过氧化物酶2（Prx2）作为一种抗氧化酶，对氧化应激诱导的细胞死亡起保护作用。然而，Prx2对PGF2α诱导的黄体退化的影响尚未见报道。在此，我们使用Prx2基因敲除（-/-）小鼠研究了Prx2在PGF2α介导的ROS诱导的黄体功能和结构退化中的作用。我们发现，与野生型（WT）细胞相比，Prx2-/- 小鼠胚胎成纤维细胞中PGF2α诱导的ROS生成显著更高，其通过激活JNK介导的凋亡信号通路诱导细胞凋亡。此外，对源自Prx2-/- 小鼠的黄体进行PGF2α处理可促进类固醇生成酶表达的降低以及JNK和caspase3的激活。与WT小鼠相比，注射PGF2α的Prx2-/- 小鼠血清孕酮水平和黄体类固醇生成酶的表达下降更快，而JNK和caspase3的激活显著增加。然而，添加抗氧化剂N-乙酰-L-半胱氨酸（NAC）可挽救受损的类固醇生成以及PGF2α诱导的JNK依赖性凋亡。这是第一项证明Prx2缺乏最终通过激活ROS依赖性JNK途径加速PGF2α诱导的黄体退化的研究。这些发现表明，Prx2在通过抑制ROS/JNK途径防止黄体退化加速方面起着关键作用。
