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A Novel Pathway for Metabolism of the Cardiovascular Risk Factor Homoarginine by alanine:glyoxylate aminotransferase 2.
- Source :
-
Scientific reports [Sci Rep] 2016 Oct 18; Vol. 6, pp. 35277. Date of Electronic Publication: 2016 Oct 18. - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Cardiovascular Diseases genetics
Cardiovascular Diseases pathology
Genome-Wide Association Study
Hep G2 Cells
Homoarginine genetics
Humans
Metabolic Networks and Pathways genetics
Metabolic Syndrome blood
Metabolic Syndrome pathology
Mice
Mice, Knockout
Mice, Transgenic
Risk Factors
Stroke genetics
Stroke pathology
Cardiovascular Diseases blood
Homoarginine blood
Metabolic Syndrome genetics
Stroke blood
Transaminases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 27752063
- Full Text :
- https://doi.org/10.1038/srep35277