Document Detail


Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure.
MedLine Citation:
PMID:  23023372     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ben Caplin; Zhen Wang; Anna Slaviero; James Tomlinson; Laura Dowsett; Mathew Delahaye; Alan Salama; ; David C Wheeler; James Leiper
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-27
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  32     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-15     Completed Date:  2013-01-29     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2892-900     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Animals
Arginine / analogs & derivatives*,  metabolism
Blood Pressure / physiology*
Disease Models, Animal
Female
Humans
Hypertension / physiopathology
Kidney / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Mitochondria / metabolism
Nitric Oxide / metabolism*
Transaminases / deficiency,  genetics,  physiology*
Grant Support
ID/Acronym/Agency:
MC_U120097118//Medical Research Council; //British Heart Foundation; //Medical Research Council; //Wellcome Trust
Chemical
Reg. No./Substance:
0/dimethylarginine; 31C4KY9ESH/Nitric Oxide; 94ZLA3W45F/Arginine; EC 2.6.1.-/Transaminases; EC 2.6.1.44/Alanine-glyoxylate transaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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