title: Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension.
abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and has been implicated in endothelial dysfunction. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), with DDAH2 representing the predominant endothelial DDAH isoform. Symmetric dimethylarginine (SDMA), also originating from arginine methylation by protein arginine methyltransferases, is an inhibitor of intracellular arginine uptake. In both chronic pulmonary hypertensive rats and patients suffering from idiopathic pulmonary arterial hypertension (IPAH; NYHA class III and IV), a marked increase in plasma ADMA and SDMA levels, as well as tissue levels of asymmetric and symmetric dimethylated proteins, was observed. Moreover, when comparing lung tissue from pulmonary hypertensive rats and IPAH patients to corresponding normal lung tissue, expression of DDAH2 was found to be reduced at both the mRNA and the protein level with no significant changes in DDAH1 expression. These findings were further supported by demonstrating a decrease in DDAH2 function in the experimental pulmonary hypertension model. Immunohistochemistry in human and rat control tissue demonstrated both isoforms of DDAH in the endothelial layer and in the alveolar epithelium. In contrast, in pulmonary hypertensive tissue, the immunoreactivity of DDAH2 in pulmonary endothelium was significantly decreased compared with DDAH1. Therefore, altogether we can conclude that enhanced dimethylarginine levels may contribute to vascular abnormalities in pulmonary arterial hypertension. Suppression of endothelial DDAH2 expression and function represents an important underlying mechanism.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Soni
authors.initials: S
authors.lastname: Pullamsetti
authors.forename: Ladislau
authors.initials: L
authors.lastname: Kiss
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Peter
authors.initials: P
authors.lastname: Haredza
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Clemens
authors.initials: C
authors.lastname: Aigner
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Jai Prakash
authors.initials: JP
authors.lastname: Muyal
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000581:Amidohydrolases / Q000032:analysis / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism*; D007527:Isoenzymes / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007527:Isoenzymes; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D016686:Monocrotaline; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase