期刊
CIRCULATION
卷 128, 期 13, 页码 1451-1461出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.112.000580
关键词
genome-wide association studies; L-arginine:glycine amidinotransferase; homoarginine; single nucleotide polymorphism; stroke
资金
- Deutsche Forschungsgemeinschaft [CH872/1-1, SFB545/A3, IS63/3-1, IS63/3-2]
- UK Stroke Association
- Stiftung Rheinland-Pfalz Wissen-schafft-Zukunft [AZ961-386261/733]
- Schwerpunkt Vaskulare Pravention (Mainz University, Boehringer Ingelheim)
- Integrierte Verbunde der Medizinischen Genomforschung-NGFN-Plus [A3 01GS0833, 01GS0831]
- Stiftung Pathobiochemie of the Deutsche Vereinte Gesellschaft fur Klinische Chemie und Laboratoriumsmedizin e.V.
- Werner-Otto-Stiftung
- Else Kroner Memorial Stipendium from the Else Kroner-Fresenius-Stiftung
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<2.1x10(-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.
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