title: In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice.
abstract: Elevated plasma concentrations of the asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse cardiovascular clinical outcomes. Both dimethylarginines can be degraded by alanine-glyoxylate aminotransferase 2 (Agxt2), which is also the key enzyme responsible for the degradation of endogenously formed β-aminoisobutyrate (BAIB). In the present study we wanted to investigate the effect of BAIB on Agxt2 expression and Agxt2-mediated metabolism of dimethylarginines. We infused BAIB or saline intraperitoneally for 7days in C57/BL6 mice via minipumps. Expression of Agxt2 was determined in liver and kidney. The concentrations of BAIB, dimethylarginines and the Agxt2-specific ADMA metabolite α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) was determined by LC-MS/MS in plasma and urine. As compared to controls systemic administration of BAIB increased plasma and urine BAIB levels by a factor of 26.5 (p<0.001) and 25.8 (p<0.01), respectively. BAIB infusion resulted in an increase of the plasma ADMA and SDMA concentrations of 27% and 31%, respectively, (both p<0.05) and a 24% decrease of plasma DMGV levels (p<0.05), while expression of Agxt2 was not different. Our data demonstrate that BAIB can inhibit Agxt2-mediated metabolism of dimethylarginines and show for the first time that endogenous Agxt2 is involved in the regulation of systemic ADMA, SDMA and DMGV levels. The effect of BAIB excess on endogenous dimethylarginine levels may have direct clinical implications for humans with the relatively common genetic trait of hyper-β-aminoisobutyric aciduria.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kittel
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Maren
authors.initials: M
authors.lastname: Mieth
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Natalia
authors.initials: N
authors.lastname: Jarzebska
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: Roman N
authors.initials: RN
authors.lastname: Rodionov
mesh_terms: D000621:Aminoisobutyric Acids / Q000008:administration & dosage*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D006146:Guanidines / Q000097:blood; D057809:HEK293 Cells; D006801:Humans; D007651:Keto Acids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000621:Aminoisobutyric Acids; D006146:Guanidines; D007651:Keto Acids; C569758:alpha-keto-delta-(NG,NG-dimethylguanidino)valeric acid; C487735:dimethylarginine; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; C033435:3-aminoisobutyric acid