Symmetric Dimethylarginine Levels Research Articles

AGXT2 and DDAH-1 genetic variants are highly correlated with serum ADMA and SDMA levels and with incidence of coronary artery disease in Egyptians.

Dimethylarginine aminodehydrolase (DDAH1) and alanine glyoxylate aminotransferase2 (AGXT2) are two enzymes that contribute in asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) metabolism. Hence they affect production and bioavailability of eNOS-derived nitric oxide (NO) and consequently healthy blood vessels. The major aims of the current study were to investigate the association of genetic variants of AGXT2 rs37369, AGXT2 rs16899974 and DDAH1 rs997251 SNPs with incidence of coronary artery disease (CAD) in Egyptians and to correlate these variants with the serum levels of ADMA and SDMA. The study included 150 subjects; 100 CAD patients and 50 healthy controls. Genotyping was performed by qPCR while the ADMA and SDMA concentrations were assayed by ELISA. Both serum ADMA and SDMA concentrations were significantly higher in CAD patients compared to controls (both p < 0.0001). Genotype distributions for all studied SNPs were significantly different between CAD patients and controls. Carriers of AGXT2 rs37369-T allele (CT + TT genotypes) and AGXT2 rs16899974-A allele (CA + AA genotypes) had 2.4- and 2.08-fold higher risk of having CAD than CC genotype in both SNPs (p = 0.0050 and 0.0192, respectively). DDAH1 rs997251 TC + CC genotypes were associated with 2.3-fold higher risk of CAD than TT genotype (p = 0.0063). Moreover, the AGXT2 rs37369 TT and AGXT2 rs16899974 AA genotypes were associated with the highest serum ADMA and SDMA while DDAH1 rs997251 CC genotype was associated with the highest ADMA. AGXT2 rs37369-T, AGXT2 rs16899974-A, and DDAH1 rs997251-C alleles represent independent risk factors for CAD in the Egyptians.

Diagnostic value of plasma tryptophan and symmetric dimethylarginine levels for acute kidney injury among tacrolimus-treated kidney transplant patients by targeted metabolomics analysis

Few literatures have evaluated the exact role of metabolomics in the identification process of potential biomarkers for acute kidney injury among the patients receiving renal transplantation. On top of this, the success of metabolomics in biomarker translation seems to lie in the robust quantitative method. As such, a single-center retrospective observational study was conducted enrolling 42 patients underwent renal transplantation with/without acute kidney injury, as well as 24 healthy volunteers, in Shanghai Changzheng Hospital. Plasma amino acid metabolic patterns for the participants were investigated by targeted UHPLC-MS/MS metabolic profiling. The most significant changes of the explored metabolites were related to the disturbance of tryptophan metabolism and arginine metabolism. Abnormal circulating tryptophan and symmetric dimethylarginine were identified to be potential biomarkers of acute kidney injury, combination of which showed a higher area under receiver-operator curve value (AUC = 0.901), improved sensitivity (0.889) and specificity (0.831) compared with creatinine only. Overall, these results revealed that targeted metabolomics analysis would be a potent and promising strategy for identification and pre-validation of biomarkers of acute kidney injury in renal transplantation patients.

Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: high plasma levels as combined risk markers for sepsis survival

BackgroundNitric oxide (NO) regulates processes involved in sepsis progression, including vascular and immune function. NO is generated by nitric oxide synthases (NOS) from L-arginine. Cellular L-arginine uptake is inhibited by symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) is a competitive inhibitor of NOS. Increased inhibitor blood concentrations lead to reduce NO bioavailability. The aim of this study was to determine whether plasma concentrations of SDMA and ADMA are markers for sepsis survival.MethodThis prospective, single center study involved 120 ICU patients with sepsis. Plasma SDMA and ADMA were measured on admission (day 1), day 3 and day 7 by mass spectrometry together with other laboratory markers. The sequential organ failure assessment (SOFA) score was used to evaluate sepsis severity. Survival was documented until day 28. Groups were compared using the Mann-Whitney U test, chi-squared test or non-parametric analysis of variance (ANOVA). Mortality was assessed using Kaplan-Meier curves and compared using the log-rank test. Specific risk groups were identified using a decision tree algorithm.ResultsMedian plasma SDMA and ADMA levels were significantly higher in non-survivors than in survivors of sepsis: SDMA 1.14 vs. 0.82 μmol/L (P = 0.002) and ADMA 0.93 vs. 0.73 μmol/L (P = 0.016). ANOVA showed that increased plasma SDMA and ADMA concentrations were significantly associated with SOFA scores. The 28-day mortality was compared by chi-square test: for SDMA the mortality was 12% in the lower, 25% in the intermediate and 43% in the 75th percentile (P = 0.018); for ADMA the mortality was 18–20% in the lower and intermediate but 48% in the 75th percentile (P = 0.006). The highest mortality (61%) was found in patients with plasma SDMA > 1.34 together with ADMA levels > 0.97 μmol/L.ConclusionsIncreased plasma concentrations of SDMA and ADMA are associated with sepsis severity. Therefore, our findings suggest reduced NO bioavailability in non-survivors of sepsis. One may use individual SDMA and ADMA levels to identify patients at risk. In view of the pathophysiological role of NO we conclude that the vascular system and immune response are most severely affected when SDMA and ADMA levels are high.

Maternal Resveratrol Therapy Protects Male Rat Offspring against Programmed Hypertension Induced by TCDD and Dexamethasone Exposures: Is It Relevant to Aryl Hydrocarbon Receptor?

Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress. Groups of four-month-old male rat offspring were studied (n = 7–8 per group): control, DEX (0.1 mg/kg i.p. from a gestational age of 16 to 22 days), TCDD (200 ng/kg in four once-weekly oral doses), DEX + TCDD, and DEX + TCDD + R (resveratrol 0.05% in drinking water throughout pregnancy and lactation). Maternal TCDD exposure aggravated prenatal DEX-induced hypertension in adult male offspring, which maternal resveratrol therapy prevented. Maternal TCDD exposure aggravated DEX-induced oxidative damage in offspring kidneys, which was prevented by resveratrol therapy. Maternal resveratrol therapy decreased asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, thereby preventing combined DEX and TCDD exposure-induced programmed hypertension. Increases in renal Ahrr and Cyp1a1 expression induced by DEX + TCDD exposure were restored by resveratrol therapy. The beneficial effects of resveratrol on DEX + TCDD-induced hypertension relate to reduced renal mRNA expression of Ren, Ace, and Agtr1a expression. Thus, the beneficial effects of resveratrol on DEX + TCDD-induced hypertension include reduction of oxidative stress, restoration of nitric oxide (NO) bioavailability, blockade of the renin–angiotensin system (RAS), and antagonizing AHR signaling pathway.

Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) patients are at high risk of developing cardiovascular disease (CVD). In RA, chronic inflammation may lead to endothelial dysfunction, an early indicator of CVD, owing to diminished nitric oxide (NO) production. Because l-arginine is the sole precursor of NO, we hypothesized that levels of l-arginine metabolic products reflecting NO metabolism are altered in patients with RA.MethodsPlasma samples from patients with RA (n = 119) and age- and sex-matched control subjects (n = 238) were used for this study. Using LC-MS/MS, we measured plasma levels of free l-arginine, l-ornithine, l-citrulline, l-NG-monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We compared global arginine bioavailability ratio (GABR) (i.e., ratio of l-arginine to l-ornithine + l-citrulline) and arginine methylation index (ArgMI) (i.e., ADMA + SDMA/MMA) in patients with RA vs. control subjects. Plasma arginase activity was measured using a sensitive arginase assay kit. The relationship of l-arginine metabolites and arginase activity to CVD risk factors was evaluated using Pearson’s chi-square test.ResultsCompared with healthy control subjects, the RA cohort showed significantly lower levels of plasma l-arginine (46.11 ± 17.29 vs. 74.2 ± 22.53 μmol/L, p < 0.001) and GABR (0.36 ± 0.16 vs. 0.73 ± 0.24, p < 0.001), elevated levels of ADMA (0.76 ± 0.12 vs. 0.62 ± 0.12 μmol/L, p < 0.001), SDMA (0.54 ± 0.14 vs. 0.47 ± 0.13 μmol/L, p < 0.001), and ArgMI (6.51 ± 1.86 vs. 5.54 ± 1.51, p < 0.001). We found an approximately fourfold increase in arginase activity (33.8 ± 1.1 vs. 8.4 ± 0.8 U/L, p < 0.001), as well as elevated levels of arginase-mediated l-arginine catalytic product l-ornithine (108.64 ± 30.26 vs. 69.3 ± 20.71 μmol/L, p < 0.001), whereas a nitric oxide synthase (NOS) catalytic product, the l-citrulline level, was diminished in RA (30.32 ± 9.93 vs. 36.17 ± 11.64 μmol/L, p < 0.001). Patients with RA with existing CVD had higher arginase activity than patients with RA without CVD (p = 0.048).ConclusionsGlobal l-arginine bioavailability was diminished, whereas plasma arginase activity, ADMA, and SDMA levels were elevated, in patients with RA compared with healthy control subjects. Plasma SDMA was associated with hypertension and hyperlipidemia in patients with RA. This dysregulated l-arginine metabolism may function as a potential indicator of CVD risk in patients with RA.

Lipopolysaccharide-induced chorioamnionitis and postnatal lung injury: The beneficial effects of L-citrulline in newborn rats

Aim of the study: The lung architecture of newborns appears to be affected by an inflammatory reaction to maternal choriodecidual layer infection. L-citrulline (L-Cit) was administered to pregnant rats exposed to intra-amniotic lipopolysaccharide (LPS)-induced chorioamnionitis to investigate its effect on neonatal lung injury. Materials and Methods: The pups were assigned to four experimental groups: 1- pups exposed to intra-amniotic NaCl but not to postnatal L-Cit (Controls); 2 - pups exposed to intra-amniotic NaCl as well as to postnatal L-Cit treatment (L-Cit group); 3 - pups exposed to prenatal LPS but not to postnatal (LPS); 4- pups exposed to prenatal LPS as well as to postnatal L-Cit treatment (LPS + L-Cit). Some pups in each group were sacrificed on postnatal (P) day 3 and others on day 7. The pups’ lungs were harvested for morphometric analysis; cytokine, arginase 1, and VEGF values were quantified. Serum arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, NG-monomethyl arginine, and homoarginine levels were determined using UPLC-MS/MS. Results: L-Cit attenuated the disruption of alveolar growth in the LPS + L-Cit group. Arginine, homo-arginine, and ADMA levels fell in the LPS treated groups. Arginine and ADMA rose at P7 in the L-Cit group whose members also showed higher VEGF levels with respect to the Controls. The Controls, instead, showed higher IL-10 and IL-1β values with respect to the L-Cit group at P7. Arginase 1 was higher in the LPS groups with respect to the Controls at P7. Conclusions: L-Cit improved alveolar and vascular growth diminishing the lung inflammatory response in the newborn rats exposed to intra-amniotic LPS. The ADMA/DDAH/NO pathway appeared to counteract proinflammatory cytokine production and to sustain macrophage migration.

Maternal Melatonin Therapy Attenuated Maternal High-Fructose Combined with Post-Weaning High-Salt Diets-Induced Hypertension in Adult Male Rat Offspring.

Consumption of food high in fructose and salt is associated with the epidemic of hypertension. Hypertension can originate from early life. Melatonin, a pleiotropic hormone, regulates blood pressure. We examined whether maternal melatonin therapy can prevent maternal high-fructose combined with post-weaning high-salt diet-induced programmed hypertension in adult offspring. Pregnant Sprague-Dawley rats received either a normal diet (ND) or a 60% fructose diet (HF) during pregnancy and the lactation period. Male offspring were on either the ND or a high-salt diet (HS, 1% NaCl) from weaning to 12 weeks of age and were assigned to five groups (n = 8/group): ND/ND, HF/ND, ND/HS, HF/HS, and HF/HS+melatonin. Melatonin (0.01% in drinking water) was administered during pregnancy and lactation. We observed that maternal HF combined with post-weaning HS diets induced hypertension in male adult offspring, which was attenuated by maternal melatonin therapy. The beneficial effects of maternal melatonin therapy on HF/HS-induced hypertension related to regulating several nutrient-sensing signals, including Sirt1, Sirt4, Prkaa2, Prkab2, Pparg, and Ppargc1a. Additionally, melatonin increased protein levels of mammalian targets of rapamycin (mTOR), decreased plasma asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine levels, and increased the l-arginine-to-ADMA ratio. The reprogramming effects by which maternal melatonin therapy protects against hypertension of developmental origin awaits further elucidation.

Arginase‐2 protects the kidney against ischemia‐reperfusion injury

Arginase‐2 (Arg2) is an enzyme converting the L‐arginine in urea and L‐ornithine. As it is expressed in extra‐hepatic tissues lacking a complete urea cycle, it may play a role in polyamines production, nitric oxide regulation or energy supply.Arg2 expression has been shown to be induced by hypoxia, in vitro and in vivo, and interestingly, its upregulation has been observed in certain animals naturally exposed to low oxygen concentration. Moreover, Arg2 overexpression has been associated with many pathological conditions, as diabetes, atherosclerosis, cardiac and renal ischemia reperfusion and cirrhosis, or after toxic compounds exposure (cadmium, cisplatin). Although Arg2 inhibition seems to improve the disease severity, the role of this upregulation remains unknown.We hypothesized that Arg2 upregulation in renal cells following an ischemic event helps the cells to overcome the occlusion‐induced stress. To address this question, we used the Pax8‐rtTA‐driven Cre expression system, allowing a conditional inactivation of Arg2 in mouse renal tubule.The conditional Arg2 knockout mice (cKO) subjected to 25‐minute renal ischemia followed by 24‐hour reperfusion show a more severe acute kidney injury (AKI) compared to Control mice and develop a transient renal Fanconi syndrome characterized by polyuria, albuminuria, aminoaciduria, hypercalcuria, hypermagnesuria and phosphaturia. When the reperfusion time increases to 2 weeks, urinary parameters normalize in both groups, but cKO mice show an increase in renal insufficiency markers compared to Control mice, with higher plasma levels of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine.Taken together, these results support a relevant role for Arg2 in renal ischemia recovery.Support or Funding InformationSwiss National Science Foundation Research grants 31003A‐149440 (to D.F.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

L-Arginine Pathway Metabolites Predict 6 Months Outcome after Acute Ischemic Stroke

Background: Increased levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are associated with endothelial dysfunction. Here, we analyzed the relationship between L-arginine pathway metabolites and functional outcome of ischemic stroke at discharge and 6 months follow-up. Methods: Plasma concentration of L-arginine, ADMA, SDMA were investigated in 46 patients at post-stroke 24 h. Outcome measures were assessed by modified Rankin scale (mRS) at hospital discharge and 6 months follow-up. According to change in mRS score during the 6 months period, patients were divided into subgroups of improved, unchanged and worsened function. Predictive role of L-arginine pathway metabolites were explored in these outcome groups. Results: Significant inverse correlations were found between initial NIHSS and the L-arginine/ADMA, the L-arginine/SDMA ratios and L-arginine plasma concentration (all p<0.05, respectively). Patients with worsened mRS by 6 months had significantly higher L-arginine plasma concentrations at 24 post-stroke hours compared to patients with improved mRS (p<0.001) and unchanged mRS (p<0.005). The L-arginine/ADMA (p<0.004) and the L-arginin/ SDMA (p<0.002) ratios at 24 h were significantly higher among patients with worsened compared to improved mRS. Besides, clinical factors, such as BMI showed negative correlation with L-arginine/ADMA; creatinine showed positive correlation with L-arginine and L-arginine/ADMA; LDL showed positive correlation with L-arginine/SDMA ratio. Plasma concentration of ADMA was significantly higher among smokers compared to non-smokers. The L-arginine/ADMA, the L-arginine/SDMA ratios and L-arginine plasma concentration negatively correlated with change of mRS between hospital discharge and at 6 months. Conclusion: Our data indicate that lower L-arginine/SDMA ratio is associated with worse outcome on the shortterm, but these patients improve on the long-term resulting in association of lower ratios with improving mRS. In contrast, patients with high L-arginine and low mRS improve fast, but will not improve or may even worsen by 6 months indicating a time-dependent biological effect.

Global arginine bioavailability ratio is decreased in patients with major depressive disorder

BackgroundMajor depressive disorder (MDD) is characterized by increased oxidative and nitrosative stress. We compared nitric oxide metabolism, i.e., the global arginine bioavailability ratio (GABR) and related serum amino acids, between MDD patients and non-depressed controls, and between remitted and non-remitted MDD patients. MethodsNinety-nine MDD patients and 253 non-depressed controls, aged 20–71 years, provided background data via questionnaires. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry to determine the serum levels of ornithine, arginine, citrulline, and symmetric and asymmetric dimethylarginine. GABR was calculated as arginine divided by the sum of ornithine plus citrulline. We compared the above measures between: 1) MDD patients and controls, 2) remitted (n=33) and non-remitted (n = 45) MDD patients, and 3) baseline and follow-up within the remitted and non-remitted groups. ResultsLower arginine levels (OR 0.98, 95% CI 0.97–0.99) and lower GABR (OR 0.13, 95% CI 0.03–0.50) were associated with the MDD vs. the non-depressed group after adjustments for potential confounders. The remitted group showed a decrease in GABR, arginine, and symmetric dimethylarginine, and an increase in ornithine after the follow-up compared with within-group baseline values. The non-remitted group displayed an increase in arginine and ornithine levels and a decrease in GABR. No significant differences were recorded between the remitted and non-remitted groups. LimitationsThe MDD group was not medication-free. ConclusionsArginine bioavailability may be decreased in MDD. This could impair the production of nitric oxide, and thus add to oxidative stress in the central nervous system.

Dimethylarginines in patients with intracerebral hemorrhage: association with outcome, hematoma enlargement, and edema

BackgroundAsymmetric dimethylarginine (ADMA)––the most potent endogenous NO-synthase inhibitor, has been regarded as mediator of endothelial dysfunction and oxidative stress. Considering experimental data, levels of ADMA and its structural isomer symmetric dimethylarginine (SDMA) might be elevated after intracerebral hemorrhage (ICH) and associated with clinical outcome and secondary brain injury.MethodsBlood samples from 20 patients with acute ICH were taken at ≤ 24 h and 3 and 7 days after the event. Nine patients had favorable (modified Rankin Scale (mRS) at 90 days 0–2) outcome, and 11 patients unfavorable outcome (mRS 3–6). Patients’ serum ADMA, SDMA, and L-arginine levels were determined by high-performance liquid chromatography–tandem mass spectrometry. Levels were compared to those of 30 control subjects without ICH. For further analysis, patients were grouped according to outcome, hematoma and perihematomal edema volumes, occurrence of hematoma enlargement, and cytotoxic edema as measured by computed tomography and serial magnetic resonance imaging.ResultsLevels of ADMA––but not SDMA and L-arginine––were elevated in ICH patients compared to controls (binary logistic regression analysis: ADMA ≤ 24 h, p = 0.003; 3 days p = 0.005; 7 days p = 0.004). If patients were grouped according to outcome, dimethylarginines were increased in patients with unfavorable outcome. The binary logistic regression analysis confirmed an association of SDMA levels ≤ 24 h (p = 0.048) and at 3 days (p = 0.028) with unfavorable outcome. ADMA ≤ 24 h was increased in patients with hematoma enlargement (p = 0.003), while SDMA ≤ 24 h was increased in patients with large hematoma (p = 0.029) and perihematomal edema volume (p = 0.023).ConclusionsOur data demonstrate an association between dimethylarginines and outcome of ICH. However, further studies are needed to confirm this relationship and elucidate the mechanisms behind.

Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease.

Chronic kidney disease (CKD) is associated with increased risk of renal and cardiovascular events. It has been claimed that endogenous methylarginines, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are contributing factors. However, earlier studies were partly contradictory and mainly focused on prevalent dialysis patients. Moreover, the potential contribution of degradation products, such as acetylated ADMA and SDMA (AcADMA and AcSDMA) and other methylarginines including L-NG-monomethylarginine (LNMMA) remains unknown. To better understand their potential pathophysiological contribution to renal and cardiovascular events, we aimed to provide a comprehensive analysis of methylarginines in a cohort of patients with non-dialysis CKD. Blood samples of 528 patients with CKD KDIGO G2 to G4 were obtained from the CARE FOR HOMe study. Baseline plasma levels of ADMA, SDMA, AcADMA, AcSDMA, and LNMMA were measured by liquid chromatography-tandem mass spectrometry. All patients were followed annually for CKD progression and for incident atherosclerotic cardiovascular events. During 5.1 ± 2.1years follow-up, 80 patients displayed CKD progression and 145 patients developed incident atherosclerotic cardiovascular events. In univariate Cox regression analyses, elevated plasma levels of all five metabolites were associated with both CKD progression and atherosclerotic cardiovascular disease. However, adjustment for confounders attenuated the prognostic implications of ADMA, LNMMA, AcADMA and AcSDMA. In contrast, patients in the highest tertile of plasma SDMA remained at highest risk for CKD progression and incident atherosclerotic cardiovascular events in fully adjusted Cox regression analyses. Our results underline a potential pathophysiological role of SDMA in CKD progression and atherosclerotic cardiovascular disease among non-dialysis CKD patients. SDMA predicts CKD progression and future atherosclerotic cardiovascular events more consistently than other methylarginines. Future experimental and clinical studies should therefore focus upon SDMA rather than upon ADMA.

Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (rs = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (rs = −0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.

Epigenetic control via allosteric regulation of mammalian protein arginine methyltransferases

Arginine methylation on histones is a central player in epigenetics and in gene activation and repression. Protein arginine methyltransferase (PRMT) activity has been implicated in stem cell pluripotency, cancer metastasis, and tumorigenesis. The expression of one of the nine mammalian PRMTs, PRMT5, affects the levels of symmetric dimethylarginine (SDMA) at Arg-3 on histone H4, leading to the repression of genes which are related to disease progression in lymphoma and leukemia. Another PRMT, PRMT7, also affects SDMA levels at the same site despite its unique monomethylating activity and the lack of any evidence for PRMT7-catalyzed histone H4 Arg-3 methylation. We present evidence that PRMT7-mediated monomethylation of histone H4 Arg-17 regulates PRMT5 activity at Arg-3 in the same protein. We analyzed the kinetics of PRMT5 over a wide range of substrate concentrations. Significantly, we discovered that PRMT5 displays positive cooperativity in vitro, suggesting that this enzyme may be allosterically regulated in vivo as well. Most interestingly, monomethylation at Arg-17 in histone H4 not only raised the general activity of PRMT5 with this substrate, but also ameliorated the low activity of PRMT5 at low substrate concentrations. These kinetic studies suggest a biochemical explanation for the interplay between PRMT5- and PRMT7-mediated methylation of the same substrate at different residues and also suggest a general model for regulation of PRMTs. Elucidating the exact relationship between these two enzymes when they methylate two distinct sites of the same substrate may aid in developing therapeutics aimed at reducing PRMT5/7 activity in cancer and other diseases.

Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

In chronic obstructive pulmonary disease (COPD), there is an activation of the L-arginine nitric oxide pathway. Pulmonary obstruction causes to elevated nitric oxide (NO) levels, which lead to higher production of the NO-inhibiting metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). We investigated the association of L-arginine, ADMA, and SDMA with clinical outcomes in a well-defined observational cohort of 150 patients with acute exacerbation of COPD. We measured L-arginine, ADMA, and SDMA by mass spectrometry in patients with pneumonic or non-pneumonic exacerbation of COPD included in a Swiss multicenter trial. We used Cox regression models to investigate the associations between blood marker levels and disease severity as well as all-cause mortality over a follow-up of 6.1years. Six-year all-cause mortality was 54%. Admission levels of ADMA and SDMA (μmolL-1) were increased in 6-year non-survivors compared to survivors' median (0.60 vs. 0.46, p=0.004; and 1.05 vs. 0.85, p=0.012). In a multivariate Cox regression analysis, ADMA was associated with long-term mortality resulting in an age- and comorbidity-adjusted hazard ratio (HR) of 4.55 (95% confidence interval 1.02-20.43, p=0.048). SDMA was only associated in univariate models and no association of L-arginine with outcome was found. ADMA was found to be an independent risk factor for long-term all-cause mortality in patients with acute exacerbation of COPD. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated in future interventional trials.

Systemic vascular resistance and endogenous inhibitors of nitric oxide synthesis in early- compared to late-onset preeclampsia: preliminary findings

ABSTRACTObjective: To examine systemic vascular resistance index (SVRI), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) levels in preeclampsia at different gestations.Methods: Twenty-four preeclamptic patients (14 at ≥ 34 weeks’) and 72 matched healthy controls were included. SVRI was calculated from impedance cardiography measurements. ADMA and SDMA levels were determined using enzyme-linked immunosorbent assay.Results: SVRI and SDMA were higher in preeclampsia overall, in early onset and late onset compared to controls. SVRI was correlated with ADMA and SDMA, respectively.Conclusions: Early-onset and late-onset preeclampsia are both characterized by increased systemic vascular resistance and elevated levels of nitric oxide synthesis inhibitors.

Influence of phenylketonuria's diet on dimethylated arginines and methylation cycle.

Phenylketonuria's (PKU) treatment based on low natural protein diet may affect homocysteine (Hcys) metabolic pathway. Hcys alteration may be related to the methylation of arginine to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which both modify nitric oxide production. The aim of this work is to evaluate the status of Hcys formation methylation cycle and ADMA and SDMA levels in patients with PKU in order to establish a potential relationship.Forty-two early diagnosed PKU patients under dietary treatment and good adherence to their diets were enrolled in this cross-sectional study. Their nutritional and biochemical profile, as well as Hcys synthesis status, ADMA and SDMA levels were analyzed and compared with a control group of 40 healthy volunteers. ADMA and SDMA were determined by high-performance liquid chromatography system coupled to triple quadrupole mass spectrometer.In this study, 23 classic PKU, 16 moderate PKU, and 3 mild HPA were enrolled. The median age was 10 years old. Median ADMA, SDMA, and Hcys concentration levels (5.1 μM [2.3–25.7], 0.35 μM [0.18–0.57], 0.43 μM [0.26–0.61], respectively) were lower in patients with PKU (P < .001 for ADMA and SDMA) whereas vitamin B12 and folate levels (616 pg/mL [218–1943] and 21 ng/mL [5–51], respectively) were higher comparing with controls. Statistically significant correlations were found between ADMA, and Phe (r = −0.504, P = .001) and Hcys (r = −0.458, P = .037) levels. Several nutrition biomarkers, such as prealbumin, 25-hydroxy vitamin D, selenium, and zinc, were below the normal range.Our study suggests that patients with PKU suffer from poor methylation capacity. Restriction of natural proteins in addition to high intake of vitamin B12 and folic acid supplementation in the dietary products, produce an impairment of methylation cycle that leads to low Hcys and ADMA levels. As a result, methylated compounds compete for methyl groups, and there is an impairment of methylation cycle due to low Hcys levels, which is related to the lack of protein quality, despite of elevated concentrations of cofactors.

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

BackgroundOxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics–related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. ObjectivesThis study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab. MethodsPlasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. ResultsAge, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p < 0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI]: 1.12 to 9.96) and 2.70 (95% CI: 1.35 to 5.41), respectively, and 0.78 (95% CI: 0.64 to 0.97) for arginine at 1 month. ConclusionsIn breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

Physical activity - related changes in ADMA and vWF levels in patients with type 2 diabetes: A preliminary study.

The activity and the role of methylarginine in diabetic patients are subject to continuous research. The mechanism through which diabetes or insulin resistance increases asymmetric dimethylarginine (ADMA) serum levels is not fully understood. Studies indicate increased ADMA serum levels in patients with hypertension, hypercholesterolemia and hyperhomocysteinemia. The aim of the study was to assess the changes in ADMA levels and its derivatives related to the current disease process, as well as the levels of selected prothrombotic factors and their changes induced by physical activity. The study included 44 patients: group A (22 patients) - patients with diabetes with no vascular complications with mean age of 55.83 ± 7.37 years; and group B (22 patients) - healthy volunteers with the mean age of 51.16 ± 6.39 years. The authors' questionnaire was used to collect sociodemographic data in the study group. Physical exercise (Nordic walking) was practiced once per day for 30 min, 5 times a week. The assessment of peripheral blood parameters was performed using the ABX MICROS OT 16-parameter hematology analyzer. Additionally, chromatographic assay of serum levels of L-arginine, ADMA and symmetric dimethylarginine (SDMA) was performed. There were statistically significant differences in ADMA levels in the respondents with type 2 diabetes vs healthy volunteers after training (0.763 ± 0.043 vs 0.532 ± 0.046; p = 0.001). ADMA and SDMA levels in diabetic patients significantly exceeded standard values.

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic, exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase 1 HO-1) induction influenced kidney and vascular function in GM-administered rats. GM (100 mg·kg-1·day-1; i.p.) was given to rats alone or together with hemin (20 mg·kg-1 on alternate days; i.p.) for 14 days. Plasma and kidney l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathological examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathological alterations in the kidney. GM elevated HO-1 protein and mRNA expressions, 4-HNE level, and MPO activity and decreased antioxidant enzyme activities and l-arginine levels in the kidney. Decreased relaxation and contraction were detected in the aorta. Hemin restored renal oxidative stress and inflammatory changes together with vascular dysfunction, but did not affect SDMA, BUN, or creatinine levels. We conclude that HO-1 induction may be effective in improving renal oxidative stress, inflammation, and vascular dysfunction mediated by GM.