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

C. U. Choe*, D. Atzler, P.S. Wild, A.M. Carter, R.H. Boger, F. Ojeda, O. Simova, M. Stockebrand, K. Lackner, C. Nabuurs, B. Marescau, T. Streichert, C. Muller, N. Luneburg, P.P. De Deyn, R.A. Benndorf, S. Baldus, C. Gerloff, S. Blankenberg, A. HeerschapP.J. Grant, T. Magnus, T. Zeller, D. Isbrandt, E. Schwedhelm

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 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.
Original languageEnglish
Pages (from-to)1451-1461
Number of pages11
JournalCirculation
Volume128
Issue number13
DOIs
Publication statusPublished - 24 Sep 2013

Keywords

  • genome-wide association studies
  • L-arginine:glycine amidinotransferase
  • homoarginine
  • single nucleotide polymorphism
  • stroke
  • MASS-SPECTROMETRIC DETERMINATION
  • CEREBRAL-ARTERY OCCLUSION
  • NITRIC-OXIDE
  • GUANIDINO COMPOUNDS
  • ISCHEMIC-STROKE
  • CARDIOVASCULAR RISK
  • MOUSE MODEL
  • BLOOD-FLOW
  • CREATINE
  • DEFICIENCY

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