title: Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  Decreased DDAH activity in the pre-eclamptic placenta might contribute to elevated ADMA levels in these patients.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. m.anderssohn@uke.de
authors.forename: Maike
authors.initials: M
authors.lastname: Anderssohn
authors.forename: Laura M
authors.initials: LM
authors.lastname: Maass
authors.forename: Anke
authors.initials: A
authors.lastname: Diemert
authors.forename: Nicole
authors.initials: N
authors.lastname: Lüneburg
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Kurt
authors.initials: K
authors.lastname: Hecher
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D005260:Female; D005312:Fetal Blood / Q000201:enzymology* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000201:enzymology* / Q000378:metabolism; D011225:Pre-Eclampsia / Q000201:enzymology* / Q000378:metabolism; D011247:Pregnancy; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; C487735:dimethylarginine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase