Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 32, Issue 12, Pages 2892-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.254078
Keywords
alanine-glyoxylate aminotransferase-2; asymmetric dimethylarginine; hypertension; kidney; NO
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Funding
- Academy of Medical Sciences
- Wellcome Trust
- Medical Research Council
- British Heart Foundation
- Academy of Medical Sciences (AMS) [AMS-SGCL5-Caplin] Funding Source: researchfish
- Medical Research Council [MC_U120097118] Funding Source: researchfish
- National Institute for Health Research [CL-2010-18-001] Funding Source: researchfish
- MRC [MC_U120097118] Funding Source: UKRI
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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). Conclusion-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. (Arterioscler Thromb Vasc Biol. 2012;32:2892-2900.)
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