Hirata Misako, Obayashi Satoshi, Sakamoto Shuichi, Aso Takeshi, Imamura Masatoshi, Azuma Hiroshi
Comprehensive Reproductive Medicine and Department of Biosystem Regulation, Institute of Biomaterials and Bioengineering, Graduate School, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda-ku, Tokyo 101-0062, Japan.
Mol Hum Reprod. 2006 Aug;12(8):513-8. doi: 10.1093/molehr/gal047. Epub 2006 May 30.
This study was designed to investigate the role of arginase in regulating myometrial contractions during gestation in the rat. Arginase activity in the myometrium was significantly decreased during the 7th-21st day of gestation, with the lowest value on the 14th day. However, the enzyme activity became significantly higher at term gestation (22nd day) than that in the non-pregnant myometrium. Arginase I protein was undetectable in the non-pregnant myometrium, at 7th and 14th day of gestation and after delivery. A slight positive signal for arginase I was detectable at 21st day of gestation. However, the protein was clearly up-regulated at term gestation (22nd day), although arginase II protein was down-regulated during gestation, with the lowest value on the 14th day. Gestational changes in arginase activity negatively correlated with those in cyclic GMP production, whereas the changes positively correlated with those in endogenous nitric oxide synthase (NOS) inhibitors and endothelin-1 (ET-1) contents. Myometrial arginase activity was inhibited by N(G)-hydroxy-L-arginine as an intermediate of NO production from L-arginine in a concentration-dependent manner. Both basal and stimulated guanylyl cyclase activities were enhanced at mid- and reduced at term gestation and after delivery, thereby partly increasing cyclic GMP production at mid- and partly decreasing the nucleotide production at term gestation and after delivery. These results suggest that the decreased arginase activity at mid-gestation possibly results from the down-regulation of arginase II protein. Whereas, the enhanced overall arginase activity at term gestation seems to be because of the induced functional arginase I in concert with the attenuated arginase II expression. The enhanced arginase activity at term gestation would be implicated in increasing myometrial contractions mediated by the increased ET-1. The increased peptide production at term gestation is possibly because of the reduced cyclic GMP production resulting from enhanced arginase activity, accumulated endogenous NOS inhibitors and attenuated guanylyl cyclase activity.
本研究旨在探讨精氨酸酶在调节大鼠妊娠期子宫肌层收缩中的作用。在妊娠第7至21天，子宫肌层中的精氨酸酶活性显著降低，在第14天达到最低值。然而，足月妊娠（第22天）时该酶活性比未孕子宫肌层中的显著更高。在未孕子宫肌层、妊娠第7天和第14天以及分娩后均未检测到精氨酸酶I蛋白。在妊娠第21天可检测到轻微的精氨酸酶I阳性信号。然而，尽管精氨酸酶II蛋白在妊娠期下调，在第14天达到最低值，但在足月妊娠（第22天）时该蛋白明显上调。精氨酸酶活性的妊娠变化与环鸟苷酸（cGMP）产生的变化呈负相关，而这些变化与内源性一氧化氮合酶（NOS）抑制剂和内皮素-1（ET-1）含量的变化呈正相关。N(G)-羟基-L-精氨酸作为L-精氨酸产生NO的中间产物，以浓度依赖的方式抑制子宫肌层精氨酸酶活性。基础和刺激型鸟苷酸环化酶活性在妊娠中期增强，在足月妊娠和分娩后降低，从而在妊娠中期部分增加cGMP产生，在足月妊娠和分娩后部分降低核苷酸产生。这些结果表明，妊娠中期精氨酸酶活性降低可能是由于精氨酸酶II蛋白下调所致。而足月妊娠时整体精氨酸酶活性增强似乎是由于诱导功能性精氨酸酶I并伴有精氨酸酶II表达减弱。足月妊娠时增强的精氨酸酶活性可能与增加ET-1介导的子宫肌层收缩有关。足月妊娠时肽产生增加可能是由于精氨酸酶活性增强、内源性NOS抑制剂积累和鸟苷酸环化酶活性减弱导致cGMP产生减少所致。
