Higher Asymmetric Dimethylarginine Levels Research Articles

Endothelial function in patients with familial Mediterranean fever-related amyloidosis and association with cardiovascular events

Secondary amyloidosis is the most important complication of FMF and endothelial function is more severely impaired. Elevated asymmetric dimethyl arginine (ADMA) may mediate the excess cardiovascular disease (CVD) risk of this group. We aimed to compare endothelial function characteristics, including ADMA, in patients with FMF-related amyloidosis and primary glomerulopathies and to define risk factors for a CVD event. We undertook a cross-sectional study with prospective follow-up including consecutive patients with FMF-related amyloidosis (n = 98) or other non-diabetic glomerulopathies (n = 102). All patients had nephrotic-range proteinuria and normal glomerular filtration rate. Flow-mediated dilatation (FMD) was assessed and ADMA levels, CRP and pentraxin 3 (PTX3) were determined. Patients were followed for cardiovascular events. Amyloidosis patients secondary to FMF showed higher levels of ADMA, CRP and PTX3 and lower FMD as compared with patients with other glomerulopathies. Cardiovascular events (n = 54) were registered during 3 years of follow-up. Increased ADMA levels and lower FMD were observed in patients with cardiovascular risk in both groups, but especially in individuals with amyloidosis. Patients with FMF-related amyloidosis have increased CVD event risk, probably related to the high ADMA levels, elevated inflammatory markers and decreased FMD measures observed in these patients.

Serum asymmetric dimethylarginine, and adiponectin as predictors of atherosclerotic risk among obese Egyptian children.

BACKGROUND: Obesity is associated with an increased risk of developing hyperinsulinemia, dyslipidemia, hypertension, premature atherosclerosis, and coronary artery disease in the future. AIM: This study is designed to assess the relationship between serum adiponectin, asymmetric dimethylarginine (ADMA), and lipid profile among Egyptian overweight and obese children. METHODS: This cross sectional case control study included 40 selected pre-pubertal overweight and obese children, 24 girls (60%) and 16 boys (40%) aged between 5 to 13 years (8.85 ± 2.7 years), from new cases attending the National nutrition institute clinic during 2013. Forty apparently healthy children of matched age and sex were recruited as a control group. RESULTS: Obese group showed highly significant higher levels of serum ADMA, triglycerides, and total cholesterol compared with healthy controls (P < 0.000 in all). However, serum adiponectin levels were highly significant lower in obese children compared to healthy controls (P < 0.000). Serum ADMA showed significant positive correlations with height, serum total cholesterol and serum triglycerides levels and significant negative correlation with the body mass index and weight for age z score. Serum adiponectin showed significant negative correlations with BMI, weight, and weight for age z score and significant positive correlation with serum triglycerides. By linear regression analysis; serum adiponectin, and serum triglycerides levels were significant predictors of high serum ADMA level (p =0.045 and 0.015 respectively). BMI, weight, height and serum triglycerides were significant predictors of low serum adiponectin levels (p = 0.005, 0.022, 0.026 and 0.015 respectively). CONCLUSIONS: Our results revealed that ADMA, Adiponectin and lipid profile can be considered as predictive biomarkers in prediction and prevention of atherosclerotic risk in the future among overweight and obese Egyptian children.

Serum Asymmetric Dimethylarginine, and Adiponectin as Predictors of Atherosclerotic Risk among Obese Egyptian Children

BACKGROUND: Obesity is associated with an increased risk of developing hyperinsulinemia, dyslipidemia, hypertension, premature atherosclerosis, and coronary artery disease in the future.AIM: This study is designed to assess the relationship between serum adiponectin, asymmetric dimethylarginine (ADMA), and lipid profile among Egyptian overweight and obese children.METHODS: This cross sectional case control study included 40 selected pre-pubertal overweight and obese children, 24 girls (60%) and 16 boys (40%) aged between 5 to 13 years (8.85 ± 2.7 years), from new cases attending the National nutrition institute clinic during 2013. Forty apparently healthy children of matched age and sex were recruited as a control group.RESULTS: Obese group showed highly significant higher levels of serum ADMA, triglycerides, and total cholesterol compared with healthy controls (P &lt;0.000 in all). However, serum adiponectin levels were highly significant lower in obese children compared to healthy controls (P &lt; 0.000). Serum ADMA showed significant positive correlations with height, serum total cholesterol and serum triglycerides levels and significant negative correlation with the body mass index and weight for age z score. Serum adiponectin showed significant negative correlations with BMI, weight, and weight for age z score and significant positive correlation with serum triglycerides. By linear regression analysis; serum adiponectin, and serum triglycerides levels were significant predictors of high serum ADMA level (p =0.045 and 0.015 respectively). BMI, weight, height and serum triglycerides were significant predictors of low serum adiponectin levels (p = 0.005, 0.022, 0.026 and 0.015 respectively).CONCLUSIONS: Our results revealed that ADMA, Adiponectin and lipid profile can be considered as predictive biomarkers in prediction and prevention of atherosclerotic risk in the future among overweight and obese Egyptian children.

Increased cerebrospinal fluid concentrations of asymmetric dimethylarginine correlate with adverse clinical outcome in subarachnoid hemorrhage patients

Elevated cerebrospinal fluid (CSF) concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been found in patients with subarachnoid hemorrhage (SAH). In addition, CSF levels of ADMA are associated with the severity of vasospasm. However, the relation between CSF ADMA levels and the clinical outcome of SAH patients is still unclear. We hypothesized that elevated ADMA levels in CSF might be related to the clinical outcome of SAH patients. CSF ADMA levels were measured in 20 SAH patients at days 3–5, days 7–9 and days 12–14 after SAH onset using high-performance liquid chromatography. Cerebral vasospasm was assessed by transcranial Doppler ultra sonography. Clinical outcome at 2year follow-up was evaluated using the Karnofsky Performance Status scale (KPS). CSF ADMA concentrations in all SAH patients were significantly increased at days 3–5 (p=0.002) after SAH, peaked on days 7–9 (p<0.001) and remained elevated until days 12–14 (p<0.001). In subgroup analysis, significant increases of CSF ADMA levels were found in patients both with and without vasospasm. The KPS scores significantly correlated with CSF levels of ADMA at days 7–9 (correlation coefficient=−0.55, p=0.012; 95% confidence interval −0.80 to −0.14). Binary logistic regression analysis indicated that higher ADMA level at days 7–9 predicted a poor clinical outcome at 2year follow-up after SAH (odds ratio=1.722, p=0.039, 95% confidence interval 1.029 to 2.882). ADMA may be directly involved in the pathological process and future adverse prognosis of SAH.

Asymmetric dimethylarginine levels in patients with cutaneous anthrax: a laboratory analysis

BackgroundAsymmetric dimethylarginine (ADMA), the main endogenous inhibitor of nitric oxide synthase, is considered to be associated with endothelial dysfunction. High ADMA levels have been shown to be related with disorders causing vascular inflammation such as hypertension, hypercholesterolemia, atherosclerosis, chronic heart failure, stroke and sepsis. Cutaneous anthrax (CA) is a serious infectious disease which may cause vasculitis. The aim of the study was to investigate the serum ADMA levels in patients with CA.MethodsA total of 35 serum samples of the patients with CA and 18 control sera were tested for ADMA levels using ADMA ELISA kit (Immunodiagnostik AG, Bensheim, Germany).ResultsADMA levels were found to be significantly higher in the patients group than the controls (p < 0.001). In addition, ADMA levels were found to be positively associated with sedimentation rates (R = 0.413; p = 0.026), and inversely associated with international normalized ratio (INR) levels (R = -0.46; p = 0.011). A cut-off value of 0.475 of ADMA had a sensitivity of 74.3%, specificity of 77.8%, and accuracy of 75.5% in the diagnosis of CA.ConclusionAlthough the exact mechanism still remains unclear, ADMA levels could be related to immune activation in CA. In addition, these data might suggest the higher ADMA levels in patients could be due to the perivascular inflammation and vasculitis in CA.

Serum reference intervals of homoarginine, ADMA, and SDMA in the study of health in Pomerania.

Low circulating homoarginine as well as high levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been associated with impaired cardiovascular (CV) outcome and mortality in patients at risk and in the general population. The present study aimed to formulate reference intervals for serum homoarginine, ADMA, and SDMA to improve risk stratification between healthy individuals and individuals at risk. We determined age- and sex-specific reference intervals for homoarginine, ADMA, and SDMA in a subgroup of 1359 healthy participants (no diabetes mellitus, CV disease, increased blood pressure, elevated blood lipids, chronic kidney disease stadium III or IV, or a body mass index >30) of the Study of Health in Pomerania (SHIP) using quantile regression analyses. Homoarginine, ADMA, and SDMA serum concentrations were measured using liquid chromatography-tandem mass spectrometry. Median age of the investigated cohort was 36 (25th; 75th percentile 28; 47) years, with 62% women. Median serum concentrations of homoarginine, ADMA, and SDMA were 2.63 (2.08; 3.32) μmol/L, 0.64 (0.57; 0.73) μmol/L, and 0.43 (0.37; 0.49) μmol/L, respectively. Serum levels of homoarginine, ADMA, and SDMA showed material age- and sex-related differences (p<0.05 for all). Overall reference ranges were 1.41-5.00 and 1.20-5.53 μmol/L (2.5th; 97.5th percentile; for men and women, respectively) for homoarginine, 0.41-0.95 and 0.43-0.96 μmol/L for ADMA, and 0.30-0.67 and 0.27-0.63 μmol/L for SDMA. We formulated for the first time homoarginine, ADMA, and SDMA reference intervals in serum. These reference intervals might be useful for individual CV risk stratification.

High Asymmetric Dimethylarginine (ADMA) Levels in Patients with Brucellosis

Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase and is considered to be associated with endothelial dysfunction. Brucellosis, a zoonotic disease caused by Brucella spp., can manifest as vasculopathy. The present study was performed to investigate the relationship between ADMA and brucellosis. Serum samples from 39 patients with an accurate diagnosis of brucellosis and from 18 healthy control individuals were included in this study. ADMA levels were significantly higher in the patient group than the controls (P < 0.001). Receiver operating characteristic (ROC) curve analysis indicated that ADMA level ≥ 0.61 had a sensitivity of 79.5 %, specificity of 88.9 %, positive predictive value of 93.9 %, and negative predictive value of 66.7 %. This is the first report of an association between brucellosis and high levels of ADMA. In conclusion, ADMA levels should be tested in brucellosis cases and that further studies to clarify the mechanism underlying the association between ADMA and brucellosis are required.

Plasma Asymmetric Dimethylarginine and Adverse Events in Patients with Atrial Fibrillation Referred for Coronary Angiogram

ObjectivesElevated plasma levels of asymmetric dimethylarginine (ADMA) have been reported to be associated with endothelial dysfunction, inflammation, and oxidative stress in multiple cardiovascular diseases. This study aimed to investigate whether ADMA was a predictor of clinical outcomes in atrial fibrillation (AF).Methods and ResultsFrom 2006-2009, 990 individuals were referred to our institution for coronary angiography. Among these patients, 141 subjects with a diagnosis of AF, including 52 paroxysmal AF (PAF) and 89 non-paroxysmal AF (non-PAF) patients, were identified as the study population. Plasma ADMA levels were measured. An adverse event was defined as the occurrence of ischemic stroke or cardiovascular death. The ADMA levels were higher in AF than non-AF patients (0.50±0.13 versus 0.45±0.07 µmol/L; p<0.001). Besides, non-PAF patients had higher ADMA levels than PAF patients (0.52±0.15 versus 0.48±0.08 µmol/L; p<0.001). During the follow-up of 30.7±14.4 months, 21 patients (14.9%) experienced adverse events, including cardiovascular death in 7 patients and ischemic stroke in 14. ADMA level, CHA2DS2-VASc score, and left atrial diameter were independent predictors of adverse events in the multivariate analysis. At a cutoff-value of 0.55 µmol/L, the Kaplan-Meier survival analysis showed that patients with a high ADMA level had a higher event rate during the follow-up period.ConclusionsA higher level of ADMA was a risk factor of adverse events in AF patients, which was independent from the CHA2DS2-VASc score. It deserves to further study whether ADMA could potentially refine the clinical risk stratification in AF.

High levels of arginine, citrulline and ADMA are independent predictors of cardiovascular disease

Purpose: Arginine is the sole nitrogen source for Nitric Oxide (NO) synthesis and citrulline is the major catabolic product of arginine. Arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of Nitric Oxide Synthase (NOS). In this study we investigated the relationships among plasma arginine levels, its catabolic end-product citrulline and the competitive inhibitor of NO biosynthesis (ADMA) and subclinical measures of atherosclerosis and as well incident Cardiovascular Disease (CVD). Methods: We performed a matched case-control study derived from the population-based Malmo Diet and Cancer Cardiovascular Cohort (MDC-CC), all included subjects were without history of CVD at baseline. During 12 years of follow-up, 253 individuals had a CVD event and were matched for age, sex and Framingham risk score with 253 controls. Arginine, citrulline and ADMA were profiled in baseline plasma samples using liquid chromatography-tandem mass spectrometry and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether arginine, citrulline and ADMA correlated with anatomical (plaque formation) abnormalities. Results: After adjustment for traditional risk factors, inflammation (hs-CRP), diabetes status and insulin resistance (HOMA-index) at baseline, each 1SD increase of arginine (1.65, 1.21-2.26; p=0.002), citrulline (1.43, 1.13-1.80; p=0.003), and ADMA (1.34, 1.04-1.72; p=0.024), were all significantly associated with increased risk of CVD after 12 years of follow-up. Furthermore, increased levels (in quartiles) of arginine, citrulline and ADMA were cross-sectionally related with presence of more than 50% stenosis of the carotid artery; (Ptrend=0.006 for arginine, Ptrend = 0.001 for citrulline and Ptrend = 0.025 for ADMA). Conclusion: This study identifies arginine, citrulline and ADMA as independent early predictors of CVD, after taking traditional risk factors for CVD, inflammation and insulin resistance into account.

Asymmetric Dimethylarginine in Exhaled Breath Condensate and Serum of Children With Asthma

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of nitric oxide synthase. By promoting the formation of peroxynitrite, ADMA is believed to contribute to several aspects of asthma pathogenesis (ie, airway inflammation, oxidative stress, bronchial hyperresponsiveness, and collagen deposition). The aim of the present study was to compare this mediator in healthy children and children with asthma using the completely noninvasive exhaled breath condensate (EBC) technique. We recruited 77 children with asthma (5-16 years of age) and 65 healthy children (5-15 years of age) who underwent EBC collection and spirometry. Serum ADMA levels and fractional exhaled nitric oxide levels were measured on the same day in a subgroup of children with asthma. EBC was collected using the Turbo-Deccs (Medivac). ADMA levels were measured using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique. ADMA could be detected in the EBC of 71 subjects with asthma and 64 healthy subjects. ADMA levels in the EBC of children with asthma were significantly higher than in the healthy control subjects (median, 0.12 [interquartile range, 0.05-0.3] vs 0.07 [0.05-0.12]; P = .017), whereas no difference emerged between the children with asthma who were or were not receiving inhaled steroid treatment. No correlation was found between serum and EBC ADMA levels (P &gt; .5). We measured ADMA in EBC by UPLC-MS/MS, a reference analytical technique. Higher ADMA levels were found in children with asthma, supporting a role for this mediator in asthma pathogenesis. This oxidative stress-related mediator also seems to be scarcely affected by steroid therapy. We speculate that ADMA might be a target for new therapeutic strategies designed to control oxidative stress in asthma.

High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction

ObjectivesLow levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute myocardial infarction possibly through impaired endothelial atheroprotection and decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) mediates endothelial function by inhibiting nitric oxide synthase activity. In patients with acute myocardial infarction, we investigated the relationship between serum levels of HDL and ADMA.Approach and ResultsBlood samples from 612 consecutive patients hospitalized for acute MI <24 hours after symptom onset were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA) and L-arginine were determined using high-performance liquid chromatography. Patients with low HDL (<40 mg/dL for men and <50 mg/dL for women) were compared with patients with higher HDL. Most patients (59%) had low HDL levels. Median ADMA levels were markedly higher in the low HDL group (0.69 vs. 0.50 µmole/L, p<0.001). In contrast, SDMA and L-arginine levels were similar for the two groups (p = 0.120 and p = 0.064). Notably, ADMA, but not SDMA or L-arginine, was inversely correlated with HDL (r = −0.311, p<0.001). In stratified analysis, this relationship was only found for low HDL levels (r = −0.265, p<0.001), but not when HDL levels were higher (r = −0.077, p = 0.225). By multivariate logistic regression analysis, ADMA level was strongly associated with low HDL levels (OR(95%CI):6.06(3.48–10.53), p<0.001), beyond traditional confounding factors.ConclusionsOur large population-based study showed for the first time a strong inverse relationship between HDL and ADMA in myocardial infarction patients, suggesting a functional interaction between HDL and endothelium, beyond metabolic conditions associated with low HDL levels.

Asymmetric dimethylarginine levels in children with sickle cell disease and its correlation to tricuspid regurgitant jet velocity

Pulmonary hypertension (PH) is an increasingly recognized life-threatening complication in sickle cell disease (SCD), with associated high mortality in adults. The prevalence of PH in children with SCD is still unknown. The etiology and pathophysiologic mechanisms are still not well understood. To assess the plasma levels of asymmetric dimethylarginine (ADMA) in children with SCD and its correlation with elevated tricuspid regurgitant jet velocity and other hemolytic markers. This study was carried out on a cohort of patients (30) with SCD and 30 healthy children as a control group. Certain investigations were carried out for all subjects: CBC, lactate dehydrogenase (LDH), ferritin, reticulocytic count, bilirubin, AST, ALT, and plasma levels of ADMA. Doppler echocardiography was carried out for all subjects. The prevalence of high tricuspid regurgitant velocity (TRV) was 30% in SCD patients. ADMA mean plasma level was significantly higher in patients than in controls (0.79±0.15μmol/L and 0.46±0.11μmol/L, respectively, P<0.001). ADMA was significantly higher in patients with high TRV than those with normal TRV (1.10±0.11μmol/L, 0.80±0.06μmol/L, respectively, P<0.001). There was a significant positive correlation between ADMA plasma levels and TRV ≥2.5m/s (r=0.475). High plasma ADMA levels may be implicated in the pathogenesis of increased tricuspid regurgitant jet velocity in children with SCD.

Endothelium and hemorheology

A number of factors are involved in the regulation and maintenance of vascular homeostasis. The role of the vascular endothelium has been identified almost three decades ago, and a number of lines of evidence provide solid support to the role of this tissue in modulating not only vascular tone, but also phenomena such as platelet, red blood cell aggregation and deformability. In turn, hemorheological characteristics have been proven to impact on the endothelial release of mediators and therefore on vascular tone. Both biochemical and physical stimuli are sensed by the endothelium as stimuli for the release of oxygen free radicals and nitric oxide. In particular, changes in blood viscosity have a direct effect on shear stress, which is believed to be the physiological stimulus for endothelial activation. These considerations have lead us to formulate an alternative hypothesis for the meaning of hyperviscosity in the setting of ischemic syndromes. While this hypothesis is supported by animal data, the evidence of cross-sectional human studies is controversial. This evidence is discussed in the present review.

Asymmetric dimethylarginine and arginine levels in patients with rheumatoid arthritis

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease and it is associated with premature atherosclerosis development. RA patients have multiple factors to develop premature atherosclerosis. Enhanced asymmetric dimethylarginine (ADMA) is considered as a risk factor for the development of atherosclerosis by inducing endothelial dysfunction. The aim of this study was to investigate the role of asymmetric dimethylarginine, arginine and citrulline levels in patients with RA and their relation to the disease activity parameters for possible role on the disease activity. Methods: 92 patients with RA and 34 healthy controls were included the study. Patients and control blood samples collected for ADMA, arginine and citrulline levels. ADMA, arginine and citrulline levels were measured by pre-column derivatization fluorescence HPLC method. CRP and ESR levels examined on the same day were taken from the patient records. Results: While ADMA levels significantly increased, arginine levels decreased in the patient group. There was no difference in citrulline levels between both groups. Only citrulline and arginine showed a weak positive correlation. ADMA, arginine, and citrulline levels showed no correlation with either biochemical parameters such as CRP or ESR, or disease activity or disease severity. Conclusion: Our study has shown that an increase in ADMA levels with the decrease in arginine levels suggests an increase in arginine turnover to ADMA. Increased ADMA levels can be used for an increased risk for premature development of atherosclerosis in patients with RA. Since high ADMA levels prevent the NO-dependent vasodilatation, a possible role of ADMA in development of premature atherosclerosis may be independent from inflammation.

The mechanism of long-term low-dose asymmetric dimethylarginine inducing transforming growth factor-β expression in endothelial cells

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, accumulates in plasma during chronic kidney disease (CKD). High plasma levels of ADMA can increase transforming growth factor-β (TGF-β) expression, related to renal fibrosis, but the precise molecular mechanism is not explicit. The present study was designed to determine the mechanism through which long-term low-dose ADMA induces TGF-β expression in endothelial cells and to investigate the molecular mechanism of its action. Human umbilical vein endothelial cells (HUVECs) were exposed to low-dose ADMA (5 and 10µmol/l) for 7passages and TGF-β expression was determined. Human renal glomerular endothelial cells (HRGECs) were exposed to high-dose ADMA (100µmol/l) which were used to clarify the molecular mechanism. The results showed that long-term low-dose ADMA (5 and 10µmol/l) increases TGF-β production in both mRNA and protein levels in HUVECs in a time-dependent manner. We confirmed that exogenous ADMA (100µmol/l) significantly enhanced stress fiber formation in HRGECs and upregulated TGF-β expression. Such effects of ADMA in HRGECs were inhibited by pre-treatment with actin depolymerizing agent, actin stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In addition, we demonstrated that ADMA (100µmol/l) significantly activated nuclear factor-κB (NF-κB) in HRGECs, which was markedly attenuated by actin depolymerizing agent, actin stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In brief, the present study demonstrated that long-term low-dose ADMA induces TGF-β expression in endothelial cells at both the gene and protein levels. The actin cytoskeleton may be involved in modulation of ADMA-induced NF-κB activation and the ensuing TGF-β expression in HRGECs.

The Association between Serum Asymmetric Dimethylarginine and Coronary Atherosclerotic Plaque in an Asymptomatic Population

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and is independently associated with poor cardiovascular outcomes. However, the direct relationship between serum ADMA level and the extent of subclinical coronary atherosclerotic plaque has never been investigated. In total, 130 consecutive asymptomatic Taiwanese subjects (mean age, 55.6±10 years), who received a health screening evaluation, were enrolled. Coronary plaque detected by computed tomography coronary angiography (CTCA) was observed in 85 (65.4%) of 130 individuals. Patients with coronary plaque had a higher ADMA level (1.16±1.15 μmol/L vs. 0.42 ± 0.33 μmol /L, p

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.

Kinetic Mechanism of Protein Arginine Methyltransferase 6 (PRMT6)

The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the mono- and dimethylation of arginine residues in a variety of proteins. Although these enzymes play important roles in a variety of cellular processes, aberrant PRMT activity is associated with several disease states, including heart disease and cancer. In an effort to guide the development of inhibitors targeting individual PRMTs, we initiated studies to characterize the molecular mechanisms of PRMT catalysis. Herein, we report studies on the kinetic mechanism of PRMT6. Initial velocity, product inhibition, and dead-end analog inhibition studies with the AcH4-21 and R1 peptides, as well as their monomethylated versions, indicate, in contrast to a previous report, that PRMT6 utilizes a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes.

Asymmetric Dimethylarginine Levels are Highly Associated With Atrial Fibrillation in an Elderly Population.

BackgroundThe importance of endothelial dysfunction in atrial fibrillation (AF) is not clarified. The aim of this study was to evaluate endothelial dysfunction assessed by selected inflammatory and haemostatic endothelial markers and nitric oxide (NO) associated variables as related to the presence of AF in an elderly population. NO is known to express anti-thrombotic as well as vasoactive properties.MethodsThis is a cross sectional study of 75-year old subjects with AF (n = 62) and control subjects in sinus rhythm (n = 124), matched for gender. Fasting blood samples were collected for analyses of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO-synthase, L-arginine, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor (vWF).ResultsLevels of vWF and ADMA were significantly higher in AF patients vs controls (P = 0.023 and P < 0.001, respectively) and the L-arginine/ADMA ratios were lower (P = 0.015), the latters still significant after adjustment for relevant covariates (P = 0.007 and P = 0.037, respectively). No significant differences in the levels of VCAM-1 and E-selectin were observed between the groups. When dividing the ADMA levels into quartiles there was a significant trend for having AF with increasing levels of ADMA (P < 0.001) with a cut-off at the 25th percentile (< 0.54 µmol/L), giving an adjusted OR for having AF of 12.46 (95% CI 3.11 - 49.86) (P < 0.001) with higher levels. A similar inverse trend was seen for the L-arginine/ADMA ratio.ConclusionOur population of 75-year-old AF patients had significantly impaired endothelial function assessed by increased levels of vWF, and more pronounced by high levels of ADMA. The results indicate AF in the elderly to be closely associated with the regulatory pathway of NO.

Inflammation and Asymmetric Dimethylarginine for Predicting Death and Cardiovascular Events in ESRD Patients

Endothelial dysfunction as assessed by asymmetric dimethylarginine (ADMA) and inflammation has been consistently linked to atherosclerosis, death, and cardiovascular (CV) events in ESRD patients. Inflammation amplifies the effect of ADMA on the severity of atherosclerosis in ESRD patients, but it is still unknown whether inflammation and ADMA interact in the high risk of death and CV events in this population. In a cohort of 225 hemodialysis patients, we investigated the interaction between inflammatory biomarkers (C-reactive protein and IL-6) and ADMA as predictors of death and CV events over an extended follow-up (13 years). During follow-up, 160 patients died, and 123 had CV events. With crude and multiple Cox regression analyses, an interaction was found between inflammation biomarkers and ADMA for explaining death and CV events in ESRD patients. The adjusted hazard ratios (HRs) for death (HR, 2.18; 95% confidence interval [CI], 1.34 to 3.54) and CV outcomes (HR, 2.59; 95% CI, 1.47 to 4.55) of patients with C-reactive protein and ADMA above the median were higher than expected in the absence of interaction under the additive model (1.15 and 1.97, respectively) and significantly higher than in patients with only one biomarker above the median. Data analyses carried out by stratifying patients according to IL-6 provided similar results. These data support the hypothesis that inflammation amplifies the risk of death and CV events associated with high ADMA levels in ESRD. These analyses further emphasize the need for intervention studies to attenuate inflammation and high ADMA levels in this population.