Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II

Chobanyan-Jürgens, Kristine; Fuchs, Anne-Jule; Tsikas, Dimitrios; Kanzelmeyer, Nele; Illsinger, Sabine; Vaske, Bernhard; Jordan, Jens; Lücke, Thomas

doi:10.1007/s00726-011-1136-3

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…An age-dependency of plasma concentrations of several amino acids had previously been described in a healthy pediatric population [23,24], nevertheless, homoarginine was not measured in those studies. Additionally, in contrast to homoarginine, plasma arginine was independent of age in our study group, in agreement with a previous report on 54 healthy children with a mean age of 11.9 ± 4.6 years [25]. …”

Section: Discussionsupporting

confidence: 93%

Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents

Jaźwińska-Kozuba¹,

Martens‐Lobenhoffer

Kruszelnicka

et al. 2013

IJMS

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Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased circulating homoarginine and elevated ornithine, a downstream product of arginase, predict adverse cardiovascular outcome. Our aim was to investigate correlates of plasma homoarginine and ornithine and their relations with carotid vascular structure in 40 healthy children and adolescents aged 3–18 years without coexistent diseases or subclinical carotid atherosclerosis. Homoarginine, ornithine, arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were measured by liquid chromatography-tandem mass spectrometry with stable isotope-labeled internal standards. Intima-media thickness (IMT) and extra-medial thickness (EMT) of common carotid arteries were estimated by B-mode ultrasound. Homoarginine correlated with arginine (r = 0.43, p = 0.005), age (r = 0.42, p = 0.007) and, weakly, with an increased arginine-to-ornithine ratio, a putative measure of lower arginase activity (r = 0.31, p = 0.048). Ornithine correlated inversely with arginine (r = −0.64, p < 0.001). IMT, EMT or their sum were unrelated to any of the biochemical parameters (p > 0.12). Thus, opposite associations of plasma homoarginine and ornithine with arginine may partially result from possible involvement of arginase, an enzyme controlling homoarginine degradation and ornithine synthesis from arginine. Age-dependency of homoarginine levels can reflect developmental changes in homoarginine metabolism. However, neither homoarginine nor ornithine appears to be associated with carotid vascular structure in healthy children and adolescents.

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Section: Discussionsupporting

confidence: 93%

Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents

Jaźwińska-Kozuba¹,

Martens‐Lobenhoffer

Kruszelnicka

et al. 2013

IJMS

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“…Our groups have investigated this pathway in healthy children and in children with renal and metabolic diseases (Lücke et al 2006a, b;Kanzelmeyer et al 2012Kanzelmeyer et al , 2014Chobanyan-Jürgens et al 2012a). The L-Arg/NO pathway in children differs from that in adults.…”

Section: Discussionmentioning

confidence: 99%

The l-arginine/NO pathway and homoarginine are altered in Duchenne muscular dystrophy and improved by glucocorticoids

et al. 2015

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The L-arginine/nitric oxide (L-Arg/NO) pathway regulates endothelial function and may play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). Yet, this pathway is poorly investigated in children suffering from DMD. Endothelial dysfunction can affect the perfusion of contracting muscles, thus leading to ischemia and hypoxia. In the present study, we tested the hypothesis that reduced NO production due to elevated synthesis of N (G),N (G)-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of NO synthesis, is a possible pathophysiological mechanism for progressive intramuscular muscle ischemia and disturbed endothelial function in children with DMD. Given the possible antagonistic action of homoarginine (hArg) on ADMA, we also analyzed this amino acid. We investigated 55 male patients with DMD and 54 healthy male controls (HC; aged 11.9 ± 4.8 vs. 11.1 ± 4.9 years, mean ± SD). Urinary creatinine and metabolites of the L-Arg/NO pathway were measured in plasma and urine by GC-MS or GC-MS/MS. Urine levels of ADMA and its major urinary metabolite dimethylamine (DMA), nitrite and nitrate (P < 0.001 for all) and hArg (P = 0.002) were significantly higher in DMD patients compared to HC, while the urinary DMA/ADMA molar ratio was lower (P = 0.002). In plasma, nitrate (P < 0.001), hArg (P = 0.002) and the hArg/ADMA ratio (P < 0.001) were lower in DMD than in HC. In plasma, ADMA (631 ± 119 vs. 595 ± 129 nM, P = 0.149), arginine and nitrite did not differ between DMD and HC. In DMD, positive correlations between ADMA, DMA or nitrate excretion and the stage of disease (according to Vignos and Thompson) were found. In DMD patients on steroid medication, lower concentrations of ADMA in plasma, and of DMA, ADMA, nitrate and hArg in urine were observed compared to non-treated patients. The L-Arg/NO pathway is impaired in DMD patients, with the disease progression being clinically negatively correlated with the extent of impairment. One of the underlying mechanisms in DMD may involve insufficient antagonism of ADMA by hArg. Steroids, but not creatine supplementation, seems to improve the L-Arg/NO pathway in DMD.

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“…Asymmetric dimethylarginine (ADMA) is an endogenous NOS inhibitor and an established cardiovascular risk factor in adults (Wu, ; Wu et al ., ). Serum concentration of ADMA is elevated in hypercholesterolaemic adults, which contributes to NO‐dependent endothelial dysfunction (Böger et al ., ; for review, see Horowitz and Heresztyn, ), but not in children with hypercholesterolaemia type II, possibly due to an increase in dimethylarginine dimethylaminohydrolase activity (Chobanyan‐Jürgens et al ., ). However, whether ADMA influences NO bioavailability in the heart, it has yet to be assessed.…”

Section: No Signalling In the Hypercholesterolaemic Heartmentioning

confidence: 97%

CardiacNOsignalling in the metabolic syndrome

Pecháňová

Varga

Cebová

et al. 2014

British J Pharmacology

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It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high-density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation. ROS/RNS can modulate cardiac NO signalling and trigger various adaptive changes in NOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardial RNS generation and decreased NO bioavailability. The increased oxidative and nitrative stress also impairs the NO-soluble guanylate cyclase (sGC) signalling pathway, limiting the ability of NO to exert its fundamental signalling roles in the heart. Enhanced ROS/RNS generation in the presence of risk factors also facilitates activation of redox-dependent transcriptional factors such as NF-κB, promoting myocardial expression of various pro-inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation of NO signalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation of NO signalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such as ACE inhibitors, certain β-blockers, and sGC activators. Better understanding of the above-mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiac NO signalling. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-6 Abbreviations ADMA, asymmetric dimethylarginine; AF, atrial fibrillation; DPP-4, dipeptidyl peptidase-4; PARP-1, poly [ADP-ribose] polymerase-1; PETN, pentaerythrityl tetranitrate; PKG, cGMP-dependent PK; ROCK, Rho-associated PK; ROS, reactive oxygen species; SNO, S-nitrosothiol; Tempol, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl; 15D-PGJ2, 15-deoxy-Δ IntroductionAlthough NO was discovered decades ago, scientific interest in this gasotransmitter is continuously increasing. Enzymic and non-enzymic formation of NO and cGMP-dependent and independent NO signalling has been reviewed in detail in the current Themed Issue (Csonka et al., 2015) and elsewhere (Ferdinandy and Schulz, 2003;Stasch et al., 2011;Tang et al., 2013;Rassaf et al., 2014). Intercellular and intracellular NO signalling is very complex, reflecting its many pathways and interactions with other free radicals to form additional signalling molecules. Reactive oxygen species (ROS), especially the superoxide anion radical, can reac...

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Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II

Cited by 12 publications

References 30 publications

Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents

Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents

The l-arginine/NO pathway and homoarginine are altered in Duchenne muscular dystrophy and improved by glucocorticoids

CardiacNOsignalling in the metabolic syndrome

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