子痫前期患者胎盘二甲基精氨酸二甲基氨基水解酶活性显著降低。

Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia.

机构信息

Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.

出版信息

Eur J Obstet Gynecol Reprod Biol. 2012 Apr;161(2):152-6. doi: 10.1016/j.ejogrb.2011.12.032. Epub 2012 Jan 28.

DOI:10.1016/j.ejogrb.2011.12.032

PMID:22285683

Abstract

OBJECTIVES

Asymmetric dimethylarginine (ADMA) is a key regulator of nitric oxide production. Elevations of ADMA have previously been associated with endothelial dysfunction in pre-eclamptic women. ADMA is degraded mainly by dimethylarginine dimethylaminohydrolase (DDAH), which is also expressed in placental tissue. Therefore, we measured placental DDAH expression and activity in pre-eclampsia and normal pregnancies in order to determine whether impairment of this enzyme in the pre-eclamptic placenta could contribute to elevations of ADMA levels in these women.

STUDY DESIGN

ADMA plasma levels were measured by LC-MS/MS in 18 pre-eclamptic patients and 28 controls. Placental DDAH activity was determined by measuring the degradation of [(2)H(6)]-labeled ADMA in tissue homogenates from placental biopsies in 15 women with pre-eclampsia and 16 controls. Placental mRNA expression of DDAH 1, DDAH 2, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and protein-arginine methyltransferase 1 (PRMT1) was determined in tissue biopsies by RT-PCR.

RESULTS

Placental DDAH activity was almost undetectable in pre-eclampsia, and it was significantly higher in controls. ADMA plasma levels were higher in pre-eclampsia as compared to normal pregnancies (0.51±0.15μmol/l vs. 0.42±0.07μmol/l; p=0.005), and the difference between maternal and fetal ADMA levels (feto-maternal ADMA gradient) was lower in pre-eclampsia (0.63±0.20μmol/l vs. 0.80±0.18μmol/l; p=0.02). Furthermore, mRNA expression levels of DDAH 2 were significantly lower in pre-eclamptic women (p=0.04), while PRMT1 expression levels were the same. In pre-eclampsia, we found only weak correlations between maternal ADMA levels and DDAH 1 (r=-0.41; p=0.22) and DDAH 2 expressions (r=-0.45; p=0.17) but a slightly stronger correlation between DDAH 2 expression and feto-maternal ADMA gradient (r=0.60; p=0.07).

CONCLUSION

Decreased DDAH activity in the pre-eclamptic placenta might contribute to elevated ADMA levels in these patients.

摘要

目的

不对称二甲基精氨酸（ADMA）是一氧化氮产生的关键调节剂。先前的研究表明，ADMA 水平升高与子痫前期妇女的血管内皮功能障碍有关。ADMA 主要通过二甲基精氨酸二甲氨基水解酶（DDAH）降解，胎盘组织中也表达 DDAH。因此，我们测量了子痫前期和正常妊娠妇女的胎盘 DDAH 表达和活性，以确定子痫前期胎盘中这种酶的损伤是否会导致这些妇女 ADMA 水平升高。

研究设计

通过液相色谱-串联质谱法（LC-MS/MS）在 18 例子痫前期患者和 28 例对照组中测量 ADMA 血浆水平。通过测量胎盘活检组织匀浆中[（2）H（6）]标记 ADMA 的降解来确定胎盘 DDAH 活性，15 例子痫前期患者和 16 例对照组患者参与了该实验。通过 RT-PCR 从组织活检中确定 DDAH1、DDAH2、内皮型一氧化氮合酶（eNOS）、诱导型一氧化氮合酶（iNOS）和蛋白精氨酸甲基转移酶 1（PRMT1）的胎盘 mRNA 表达。

结果

子痫前期患者的胎盘 DDAH 活性几乎检测不到，而对照组的 DDAH 活性明显更高。与正常妊娠相比，子痫前期患者的 ADMA 血浆水平更高（0.51±0.15μmol/l 比 0.42±0.07μmol/l；p=0.005），并且子痫前期患者的母体和胎儿 ADMA 水平之间的差异（胎母 ADMA 梯度）较低（0.63±0.20μmol/l 比 0.80±0.18μmol/l；p=0.02）。此外，子痫前期妇女的 DDAH2mRNA 表达水平明显降低（p=0.04），而 PRMT1 表达水平则相同。在子痫前期中，我们仅发现母体 ADMA 水平与 DDAH1（r=-0.41；p=0.22）和 DDAH2 表达（r=-0.45；p=0.17）之间存在较弱的相关性，但 DDAH2 表达与胎母 ADMA 梯度之间的相关性稍强（r=0.60；p=0.07）。