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Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure.

Caplin, B, Wang, Z, Slaviero, A, Tomlinson, J, Dowsett, L, Delahaye, M, Salama, A, International Consortium for Blood Pressure Genome-Wide Associat, , Wheeler, DC and Leiper, J (2012) Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure. Arterioscler Thromb Vasc Biol, 32 (12). pp. 2892-2900.

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Abstract

OBJECTIVE: Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. METHODS AND RESULTS: In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). CONCLUSIONS: Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.

Item Type: Article
Authors :
NameEmailORCID
Caplin, BUNSPECIFIEDUNSPECIFIED
Wang, ZUNSPECIFIEDUNSPECIFIED
Slaviero, Aa.slaviero@surrey.ac.ukUNSPECIFIED
Tomlinson, JUNSPECIFIEDUNSPECIFIED
Dowsett, LUNSPECIFIEDUNSPECIFIED
Delahaye, MUNSPECIFIEDUNSPECIFIED
Salama, AUNSPECIFIEDUNSPECIFIED
International Consortium for Blood Pressure Genome-Wide Associat, UNSPECIFIEDUNSPECIFIED
Wheeler, DCUNSPECIFIEDUNSPECIFIED
Leiper, JUNSPECIFIEDUNSPECIFIED
Date : December 2012
Identification Number : 10.1161/ATVBAHA.112.254078
Uncontrolled Keywords : Adult, Animals, Arginine, Blood Pressure, Disease Models, Animal, Female, Humans, Hypertension, Kidney, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mitochondria, Nitric Oxide, Transaminases
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:29
Last Modified : 17 May 2017 14:49
URI: http://epubs.surrey.ac.uk/id/eprint/828014

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