A novel pathway for metabolism of the cardiovascular risk factor homoarginine by alanine:glyoxylate aminotransferase 2

Rodionov, R. N. et al. (2016) A novel pathway for metabolism of the cardiovascular risk factor homoarginine by alanine:glyoxylate aminotransferase 2. Scientific Reports, 6(1), 35277. (doi: 10.1038/srep35277) (PMID:27752063) (PMCID:PMC5082758)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Rodionov, R. N., Oppici, E., Martens-Lobenhoffer, J., Jarzebska, N., Brilloff, S., Burdin, D., Demyanov, A., Kolouschek, A., Leiper, J., Maas, R., Cellini, B., Weiss, N., and Bode-Böger, S. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Scientific Reports 6(1)L35277
Publisher Policy:Reproduced under a Creative Commons License

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