Abstract 11773: Association Between Homoarginine and Acute Ischaemic Stroke - The Role of L-Arginine:Glycine-Amidinotransferase (AGAT)
Background: The amino acid homoarginine is an alternative substrate for nitric oxide synthase, thereby interacting with vascular tone and platelet function. Recently, impaired homoarginine has been identified as a CV risk marker. The present study aimed to elucidate the mechanistic link between homoarginine, stroke and the enzymatic regulation of homoarginine plasma concentrations.
Methods: We investigated 1) the predictive value of homoarginine in 389 acute ischemic stroke patients for all-cause mortality (Leeds Stroke Study, LSS). 2) The association between genetic variations and homoarginine plasma concentrations in a genome-wide association (GWA) analysis in 3,500 participants of the Gutenberg Health Study (GHS) and 3) the role of the homoarginine/L-arginine:glycine-amidinotransferase (AGAT)-pathway, in AGAT-/- mice subjected to temporary middle cerebral artery occlusion (tMCAO) as a model of experimental ischaemic stroke.
Results: In the LSS, homoarginine plasma concentrations were higher in patients who survived compared with patients who died during 7.4 year follow-up (1.18 [1.11, 1.26] vs. 0.90 [0.84, 0.96] µmol/L; p<0.001). In multivariable Cox proportional hazard models homoarginine was independently associated with survival (HR for a 1 SD increase in loghomoarginine: 0.79 [95% CI: 0.64, 0.96]; p=0.019). In GWA analysis the three top SNPs (rs10519022, rs9783731, rs1145077) associated with plasma homoarginine concentrations were in the AGAT gene (p<10-9 for all); these associations were replicated in the LSS. In contrast to wildtype (wt) littermates AGAT-/- mice are lacking homoarginine in plasma (0.11 (±0.05) vs. <0.02 µmol/L; p<0.05). In mice subjected to tMCAO, AGAT-/- mice showed two fold increased stroke volumes vs. wt (56±17 vs. 23±7%, p<0.01).
Conclusion: We identified AGAT as the enzyme responsible for homoarginine synthesis in man and mice, and our results link homoarginie and AGAT to the pathological basis of acute ischemic stroke. The determination of AGAT genotype and/or homoarginine plasma concentration could be useful for secondary CV risk prediction. Moreover, increasing homoarginine plasma concentrations might be a novel therapeutic strategy for ameliorating the impact of ischaemic stroke.
- © 2011 by American Heart Association, Inc.