Enhanced levels of asymmetric dimethylarginine in a serum of middle age patients with myelodysplastic syndrome
© Štikarová et al.; licensee BioMed Central Ltd. 2013
Received: 17 July 2013
Accepted: 17 August 2013
Published: 19 August 2013
Myelodysplastic syndromes (MDS) are hematological malignancies of unclear etiology where oxidative stress may contribute to the pathogenesis. Methylarginines, naturally occurring inhibitors of NO synthase, can increase superoxide generation from uncoupled NO synthase. We found significant increase in concentrations of asymmetric dimethylarginine (0.84 ± 0.32 μmol/L, p = 0.0022) and malondialdehyde (0.77 ± 0.11 μmol/L, p < 0.001) in sera of MDS patients vs controls (asymmetric dimethylarginine: 0.56 ± 0.16 μmol/L, malondialdehyde: 0.52 ± 0.07 μmol/L). On the contrary, nitrites concentrations were significantly decreased in MDS patients (1.71 ± 0.46 μmol/L, p = 0.0028) vs controls (2.16 ± 0.38 μmol/L). We suppose that the oxidative stress in MDS is enhanced due to methylated arginines influence on NO synthase activity impairment.
To the editor
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders, characterized by ineffective hematopoiesis and a high risk of transformation into acute myeloid leukemia. It has been determined that oxidative stress plays a role in the initialization and disease progression . The reactive oxygen species may oxidize tetrahydrobiopterin resulting into nitric oxide synthase (NOS) uncoupling and preferential formation to superoxide anion radical. It was found that methylarginines (asymmetric dimethylarginine - ADMA, NG-monomethyl-L-arginine - MMA and symmetric dimethylarginine - SDMA), naturally occurring inhibitors of NOS , can profoundly increase superoxide generation from uncoupled NOS . Free methylated arginines, capable of inhibiting NOS , are formed exclusively by the sequence of methylation of arginine residues of proteins, followed by proteolysis of these proteins. Protein arginine methylation is in mammalian cells carried out by protein arginine methyltransferases (PRMTs); many of them show links to cancer .
Baseline characteristics of MDS patients and healthy controls
aSerum iron [μmol/L]
aSerum ferritin [μg/L]
Concentrations of methylated arginines in sera of MDS patients and healthy controls
0.84 ± 0.32
0.56 ± 0.16
0.54 ± 0.18
0.42 ± 0.14
0.14 ± 0.05
0.10 ± 0.03
1.77 ± 1.06
2.32 ± 1.26
46.68 ± 14.96
42.19 ± 12.31
0.77 ± 0.11
0.52 ± 0.07
1.71 ± 0.46
2.16 ± 0.38
Our results showed significantly increased oxidative stress even in MDS patients characterized by moderately enhanced iron and serum transferrin concentrations. Resulting shift of overexpressed  NO synthase activity in favour of superoxide production at the expense of nitric oxide synthesis (reflected by nitrites concentrations ) was further augmented at the presence of methylated arginines. Therefore, oxidative stress in MDS patients could be explained by a positive feedback of both superoxide and methylated arginines on original NOS activity impairment. Moreover, recently proposed PRMT-specific inhibitors  might have a therapeutic effect on leukemia also by oxidative stress reduction.
Nitric oxide synthase
protein arginine methyltransferase.
This work was supported by Grant CZ.2.16/3.1.00/24001 of the EU ERDF OPPK, by P205/12/G118 of Centrum Excellence, by Grant KAN200670701 from the Academy of Sciences, Czech Republic and by the Ministry of Health, Czech Republic project for the conceptual development of research organization, VZ MZ 00002373601 IHBT.
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