title: A Novel Pathway for Metabolism of the Cardiovascular Risk Factor Homoarginine by alanine:glyoxylate aminotransferase 2.
abstract: Low plasma concentrations of L-homoarginine are associated with an increased risk of cardiovascular events, while homoarginine supplementation is protective in animal models of metabolic syndrome and stroke. Catabolism of homoarginine is still poorly understood. Based on the recent findings from a Genome Wide Association Study we hypothesized that homoarginine can be metabolized by alanine:glyoxylate aminotransferase 2 (AGXT2). We purified human AGXT2 from tissues of AGXT2 transgenic mice and demonstrated its ability to metabolize homoarginine to 6-guanidino-2-oxocaproic acid (GOCA). After incubation of HepG2 cells overexpressing AGXT2 with isotope-labeled homoarginine-d4 we were able to detect labeled GOCA in the medium. We injected wild type mice with labeled homoarginine and detected labeled GOCA in the plasma. We found that AGXT2 knockout (KO) mice have higher homoarginine and lower GOCA plasma levels as compared to wild type mice, while the reverse was true for AGXT2 transgenic (Tg) mice. In summary, we experimentally proved the presence of a new pathway of homoarginine catabolism - its transamination by AGXT2 with formation of GOCA and demonstrated that endogenous AGXT2 is required for maintenance of homoarginine levels in mice. Our findings may lead to development of novel therapeutic approaches for cardiovascular pathologies associated with homoarginine deficiency.
authors.affiliation: University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Roman N
authors.initials: RN
authors.lastname: Rodionov
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Oppici
authors.affiliation: Institute of Clinical Pharmacology, Otto-von-Guericke University, Leipziger Str.44, 39120 Magdeburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.affiliation: University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Jarzebska
authors.affiliation: University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Brilloff
authors.affiliation: Department of General Physiology, Saint-Petersburg State University, University Embankment, 7-9, 199034 Saint-Petersbug, Russia.
authors.forename: Dmitrii
authors.initials: D
authors.lastname: Burdin
authors.affiliation: Department of General Physiology, Saint-Petersburg State University, University Embankment, 7-9, 199034 Saint-Petersbug, Russia.|Institute of Highly Pure Biopreparations, 7 Pudozhskaya str., 197110 Saint-Petersburg, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Demyanov
authors.affiliation: University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kolouschek
authors.affiliation: Nitric Oxide Signalling Group, MRC Clinical Sciences Centre (CSC), Du Cane Road, W12 0NN, London.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, W12 0NN, London.
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Fahrstr. 17, 91054 Erlangen, Germany.
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cellini
authors.affiliation: University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.affiliation: Institute of Clinical Pharmacology, Otto-von-Guericke University, Leipziger Str.44, 39120 Magdeburg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics / Q000473:pathology; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D006709:Homoarginine / Q000097:blood* / Q000235:genetics; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012307:Risk Factors; D020521:Stroke / Q000097:blood* / Q000235:genetics / Q000473:pathology; D000637:Transaminases / Q000235:genetics*
chemical_list: D006709:Homoarginine; D000637:Transaminases; C023067:glyoxylate aminotransferase; C019635:Alanine-glyoxylate transaminase