Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia

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.