Homoarginine Levels Are Regulated by l -Arginine:Glycine Amidinotransferase and Affect Stroke Outcome

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. 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.

Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study

“…Furthermore, a possible harmful effect of elevated l-homoarginine has been proposed (Van der Zwan et al 2013), which may imply a U-shaped relationship between l-homoarginine and eGFR. Genome-wide association studies and knockout experiments identified l-arginine:glycine amidinotransferase (AGAT) as the biosynthetic enzyme for l-homoarginine (Choe et al 2013;Kleber et al 2013), and a distinct allele frequency for single-nucleotide polymorphisms was identified in black participants, correlating with higher l-homoarginine concentrations in black men and women (Atzler et al 2014). Whether these findings are of pathophysiologic relevance in cardiovascular disease deserves further investigation.…”

Homoarginine, arginine, and relatives: analysis, metabolism, transport, physiology, and pathology

“…Guanidinoacetate methyltransferase (GAMT) methylates guanidinoacetate to form creatine. Creatine inhibits AGAT-catalyzed synthesis of l-homoarginine in vivo in mice (Choe et al 2013;Kayacelebi et al 2015b), presumably by reacting with the SH group of AGAT-Cys 407 disorders. ADMA is generally believed to exclusively exert its biological actions by inhibiting NOS-catalyzed synthesis of NO from Arg.…”

“…These issues include the biosynthesis and metabolism of hArg. There is strong evidence from in vitro and in vivo animal experiments (Choe et al 2013) and valuable information from very few human individuals (Davids et al 2012) that arginine:glycine amidinotransferase (AGAT; EC 2.1.4.1) is the enzyme that is mainly responsible for the synthesis of hArg. Yet, the precise mechanism of this biosynthetic route and the factors which may modulate this reaction are essentially unknown.…”

Serum and cerebrospinal fluid concentrations of homoarginine, arginine, asymmetric and symmetric dimethylarginine, nitrite and nitrate in patients with multiple sclerosis and neuromyelitis optica

“…Changes in NO bioavailability and in circulating ADMA, SDMA and hArg concentrations have been intensively studied in cardiovascular diseases (CVD) in recent decades establishing high ADMA and low hArg concentrations as cardiovascular risk factors associated with cardiovascular and all-cause mortality (Böger et al 2009;März et al 2010;Pilz et al 2011;Drechsler et al 2011;Choe et al 2013;Atzler et al 2013Atzler et al , 2014Pilz et al 2014Pilz et al , 2015a. Moreover, recent studies on rheumatoid arthritis have demonstrated a positive association of inflammatory burden with ADMA levels independent of classical CVD risk factors (Sandoo et al 2014), suggesting a pivotal role of altered NO metabolism in chronic inflammatory diseases.…”