Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies

TY - JOUR

T1 - Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies

AU - Choe, Chi-un

AU - Atzler, Dorothee

AU - Wild, Philipp S

AU - Carter, Angela M

AU - Böger, Rainer H

AU - Ojeda Echevarria, Francisco Miguel

AU - Simova, Olga

AU - Stockebrand, Malte

AU - Lackner, Karl

AU - Nabuurs, Christine

AU - Marescau, Bart

AU - Streichert, Thomas

AU - Müller, Christian

AU - Lüneburg, Nicole

AU - De Deyn, Peter P

AU - Benndorf, Ralf A

AU - Baldus, Stephan

AU - Gerloff, Christian

AU - Blankenberg, Stefan

AU - Heerschap, Arend

AU - Grant, Peter J

AU - Magnus, Tim

AU - Zeller, Tanja

AU - Isbrandt, Dirk

AU - Schwedhelm, Edzard

PY - 2013/9/24

Y1 - 2013/9/24

N2 - 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 with stroke pathology and outcome.METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice 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 to be 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.

AB - 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 with stroke pathology and outcome.METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice 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 to be 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.

KW - Adult

KW - Aged

KW - Amidinotransferases

KW - Animals

KW - Arginine

KW - Cohort Studies

KW - Disease Models, Animal

KW - Female

KW - Genome-Wide Association Study

KW - HEK293 Cells

KW - Homoarginine

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Stroke

KW - Treatment Outcome

U2 - 10.1161/CIRCULATIONAHA.112.000580

DO - 10.1161/CIRCULATIONAHA.112.000580

M3 - SCORING: Journal article

C2 - 24004504

VL - 128

SP - 1451

EP - 1461

JO - CIRCULATION

JF - CIRCULATION

SN - 0009-7322

IS - 13

ER -