Homoarginine Levels are Regulated by L-Arginine: Glycine Amidinotransferase and Affect Stroke Outcome: Results from Human and Murine Studies

BACKGROUND: Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism in stroke pathology and outcome. METHODS AND RESULTS: Increasing homoarginine levels independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years follow-up, HR for 1 SD homoarginine: 0.79 [95% CI:0.64,0.96], P=0.019, n=389). Homoarginine was also independently associated with the NIHSS+age score and 30-day mortality after ischemic stroke. (P<0.05, n=137). Genome-wide association study (GWAS) revealed that plasma homoarginine strongly associated with SNPs in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1x10-8, n=2,806) and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we employed two genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: i) an AGAT deletion (AGAT-/-) and ii) a guanidinoacetate N-methyltransferase deletion, (GAMT-/-) causing AGAT upregulation. As suggested by the GWAS, homoarginine was absent in AGAT-/-, and increased in GAMT-/- mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT-/- mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT-/- mice was decreased compared with controls. CONCLUSIONS: Low homoarginine appears related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.