Objectives: 

The clinical relevance of symmetric dimethylarginine (SDMA) was recently shown by us in studies investigating the influence of dimethylarginines on acute ischemic stroke. SDMA showed significant associations with detrimental outcome and mortality. SDMA is mainly excreted unchanged by kidney. In the present study, we investigate whether the adverse effects of this cardiovascular risk factor can be influenced and attempt to identify potential enzymatic degradation pathways, which could serve as future therapeutic targets.

Materials: 

To identify enzymes involved in SDMA degradation we performed a genome-wide association study in the community-based Offspring Cohort of the Framingham Heart Study (FHS). Confirmatory experiments were performed in human embryonic kidney cells (HEK), which were transfected with pcDNA3.1 vectors containing human wild-type or variant (rs37369) of alanine glyoxylate aminotransferase 2 (AGXT2). The localization of AGXT2 was carried out by confocal microscopy and Western Blot. For further examination of SDMA metabolism a spectroscopic activity assay was established.

Results: 

Whole genome scan in the FHS (n=2992) identified several genome-wide significant (p<5x10-8) variants at a locus on chromosome 5p13 (1.95x10-14-4.93x10-8) including one missense variant (rs37369). The enzyme associated with SDMA at this locus is designated as AGXT2 and is mainly expressed in kidney and liver. AGXT2 overexpressing cells metabolized SDMA more avidly than control cells; cells overexpressing the variant were not able to convert SDMA to the same extent (determined by AGXT2 activity; p=0.034). We also confirmed localization of AGXT2 in mitochondria of HEK cells.

Conclusions: 

We conclude that AGXT2 is an enzyme involved in SDMA degradation. Mutation of AGXT2 results in impaired SDMA metabolism; therefore, presence of rs37369 variant is associated with elevated SDMA plasma levels. AGXT2 might be a promising novel target for pharmacotherapeutic intervention.