title: Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.
abstract: 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.
  
  
  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.
authors.affiliation: Departments of Neurology (C.C., O.S., C.G., T.M.), Experimental Neuropediatrics (C.C., M.S., D.I.), Department of Clinical Pharmacology and Toxicology (D.A., R.H.B., N.L., R.A.B., E.S.), and German Center for Cardiovascular Research (D.A., P.S.W., R.H.B., S.B., T.Z., E.S.), Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (F.O., C.M., S. Baldus, S. Blankenberg, T.Z.); Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.S.); Department of Cardiology and Angiology (P.S.W.), Gutenberg Health Study (P.S.W.), and Department of Clinical Chemistry (K.L.), Johannes Gutenberg University, Mainz, Germany; Experimental Neurophysiology, University Hospital Cologne, Köln, Germany (D.I.); German Center for Neurodegenerative Diseases, Bonn, Germany (D.I.); Department of Clinical Pharmacy and Pharmacotherapy, Martin-Luther-University Halle Wittenberg, Halle Germany (R.A.B.); Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK (A.M.C., P.J.G.); Department of Radiology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands (C.N., A.H.); and Laboratory of Neurochemistry and Behavior, Born-Bunge Foundation, University of Antwerp, Antwerp, Belgium (B.M., P.P. De D.).
authors.forename: Chi-un
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authors.lastname: Baldus
authors.forename: Christian
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authors.lastname: Gerloff
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authors.lastname: Blankenberg
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authors.lastname: Heerschap
authors.forename: Peter J
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authors.lastname: Grant
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Dirk
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authors.lastname: Isbrandt
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
mesh_terms: D000328:Adult; D000368:Aged; D000579:Amidinotransferases / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000235:genetics*; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006709:Homoarginine / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D020521:Stroke / Q000175:diagnosis / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D006709:Homoarginine; D001120:Arginine; D000579:Amidinotransferases; C020681:glycine amidinotransferase
keywords: L-arginine:glycine amidinotransferase; genome-wide association studies; homoarginine; single nucleotide polymorphism; stroke