The role of l-arginine/l-homoarginine/nitric oxide pathway for aortic distensibility and intima-media thickness in stroke patients

Abstract

Asymmetric dimethylarginine (ADMA) and L-homoarginine (hArg) are L-arginine (Arg) metabolites derived from different pathways. Protein arginine N-methyltransferase (PRMT) and subsequent proteolysis of proteins containing methylarginine residues release ADMA. Arginine:glycine amidinotransferase (AGAT) converts Arg to hArg and guanidinoacetate (GAA). While high concentrations of ADMA and low concentrations of hArg in the blood have been established as cardiovascular risk markers, the cardiovascular relevance of GAA is still unexplored. Arg and hArg are substrates and ADMA is an inhibitor of nitric oxide (NO) synthase (NOS). The cardiovascular effects of ADMA and hArg have been related to NO, a potent endogenous vasodilator. ADMA and hArg are considered to exert additional, not yet explored, presumably NO-unrelated effects and to act antagonistically in the renal and cardiovascular systems. Although the physiological role of Arg, ADMA, hArg and NO for endothelial function in small- and medium-sized arteries has been intensively studied in the past, the clinical relevance of aortic wall remodeling still remains unclear. Here, we evaluated potential relation between aortic distensibility (AD) or aortic intima-media thickness (aIMT) and circulating ADMA, hArg, GAA, and the NO metabolites nitrite and nitrate in the plasma of 78 patients (24 females, 54 males; aged 59 ± 14 years) with recent ischemic stroke or transient ischemic attack (TIA). All biochemical parameters were determined by stable-isotope dilution gas chromatography-mass spectrometry. AD and aIMT were measured by transesophageal echocardiography. Arg, hArg, ADMA and GAA median plasma concentrations (µM) were determined to be 61, 1.43, 0.50 and 2.16, respectively. hArg, ADMA and GAA correlated closely with Arg. Nitrite, nitrate and creatinine median plasma concentrations (µM) were 2.49, 48.7, and 84.1, respectively. Neither AD (2.61 vs. 1.85 10 × cm × dyn, P = 0.064) nor aIMT (1.25 vs. 1.13 mm, P = 0.596) differed between females and males. The hArg/ADMA molar ratio (r = -0.351, P = 0.009), nitrate (r = 0.364, P = 0.007) and nitrite (r = 0.329, P = 0.015) correlated with aIMT but not with AD. Arg, hArg, ADMA and GAA correlated with aIMT but not with AD. The results demonstrate a strong relation between the Arg/NO pathway and aortic atherosclerosis but not with AD suggesting different mechanisms underlying the two aspects of aortic wall remodeling.

Homoarginine and all‐cause mortality: A systematic review and meta‐analysis

“…Recent studies have investigated cross-sectional associations between homoarginine concentrations and markers of vascular/metabolic homoeostasis and cardiac function. Haghikia et al 14 reported nonsignificant associations between plasma homoarginine concentrations and aortic distensibility and intima-media thickness in 78 patients with a recent cerebrovascular event. Pilz et al 15 observed significant inverse associations between serum homoarginine concentrations and N-terminal pro-B-type natriuretic peptide (P < .001) and midregional pro-adrenomedullin (P < .001), biomarkers of diastolic dysfunction and heart failure, in 1396 patients with preserved left ventricular ejection fraction.…”

“…4,5 There is emerging evidence that homoarginine, a basic amino acid that is synthesized from L-arginine by the enzyme arginine:glycine amidinotransferase, exerts beneficial effects not only on endothelial function but also on markers of vascular homoeostasis and cardiac function. [14][15][16][17][18] Therefore, one can hypothesize that higher homoarginine concentrations might translate into better clinical outcomes in subjects with various degrees of cardiovascular risk. 12,13 Circulating homoarginine concentrations have shown inverse associations with surrogate markers of vascular and cardiac dysfunction.…”

“…12,13 Circulating homoarginine concentrations have shown inverse associations with surrogate markers of vascular and cardiac dysfunction. [14][15][16][17][18] Therefore, one can hypothesize that higher homoarginine concentrations might translate into better clinical outcomes in subjects with various degrees of cardiovascular risk.…”

l ‐Homoarginine supplementation prevents diabetic kidney damage

“…Choe et al () reported that elevated l ‐homoarginine levels were associated with reduced all‐cause mortality in patients with ischemic stroke and that low l ‐homoarginine appears to be related to poor outcome after ischemic stroke. Moreover, l ‐homoarginine supplementation significantly improved cerebral damage and neurological deficits in mouse models with stroke (Haghikia et al ).…”

“…Plasma concentrations of homoarginine are inversely correlated with the risk of cardiovascular disease and overall mortality (Marz et al ; Jud et al ), increased risk for fatal strokes (Haghikia et al ), congestive heart failure and left ventricular hypertrophy (Atzler et al , , Pilz et al ; Bahls et al ), aging (Marz et al ; Atzler et al ), smoking (Zwan et al ; Sobczak et al ; Atzler et al ; Vogl et al ), body mass index (Marz et al ; Atzler et al ; Pilz et al ), and pregnancy (Valtonen et al ). In addition, the effects of homoarginine on nitric oxide (NO) synthesis have been linked with increased risk of stroke and atherosclerosis as a reduction in homoarginine levels increased the aortic intima‐media thickness (Haghikia et al ). Low plasma homoarginine concentration is also significantly associated with the progression of chronic kidney disease (Drechsler et al ) and progression to dialysis and mortality (Ravani et al ), indicating that low plasma homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression.…”