Serum Asymmetric Dimethylarginine Levels Research Articles

Value of Serum Asymmetric Dimethylarginine (ADMA) As a Novel Biomarker for Uveitis in Behçet’s Disease

ABSTRACT Purpose To evaluate the serum asymmetric dimethylarginine (ADMA) level as a biomarker for uveitis in Behçet’s Disease (BD). Methods In this cross-sectional study, two groups of BD patients were examined: 33 with uveitis and 27 without uveitis. All patients were clinically evaluated, with disease activity measured by Behçet’s Disease Current Activity Form (BDCAF) score. They also underwent thorough ophthalmic evaluation, and routine laboratory investigations, including serum ADMA. Results Patients with BD who experienced active or inactive uveitis had higher levels of serum ADMA compared to those without uveitis. Anterior (ρ = 0.34, p < 0.01), posterior (ρ = 0.3, p < 0.05), and pan uveitis (ρ = 0.35, p < 0.01) were significantly correlated with serum ADMA levels. However, there was no significant correlation between ADMA and other BD manifestations. ROC curve analysis showed that increased serum ADMA levels in BD patients predicted uveitis with a sensitivity of 61.8%, specificity of 96.2%, and AUC of 0.78(95% CI: 0.66–0.9, p < 0.001). Conclusion Serum ADMA level can serve as a novel biomarker of uveitis in BD and its severity with good diagnostic accuracy, regardless of its site or activity.

Evaluation of Asymmetric Dimethylarginine, Malondialdehyde, and Vitamin Levels of Borderline Personality Disorder Patients With and Without Self-Mutilation.

Believing that oxidative stress may be increased in borderline personality disorder (BPD) patients with self-mutilating behaviors (SMB), we aimed to measure serum asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) levels in these patients. The study included 60 patients diagnosed with BPD and 30 healthy controls. BPD patients were divided into two groups: 30 female patients with SMB and 30 female patients with no-self-mutilating behavior (NSMB). ADMA, MDA, vitamin A, and vitamin E levels were analyzed. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were conducted with the participants. Serum ADMA and MDA levels were higher in SMB and NSMB group compared to control group. Serum vitamin E levels were also lower in the SMB group compared to the control group. Positive correlations were determined between both ADMA and MDA, and between BDI and BAI scores. Also, BAI scores were statistically higher in SMB group compared to NSMB group. It was discovered that levels of ADMA and MDA, which reflected oxidative stress, were elevated in patients with BPD who exhibited SMB. Accordingly, future studies should investigate the role of oxidative stress in a more comprehensive way in terms of the different mechanisms underlying and treatments involved in borderline personality disorder.

Relationships between polymorphisms in keratin genes and Alzheimer’s disease phenotypes.

AbstractBackgroundKeratins are genetically polymorphic and are the largest subset of intermediate filaments. Keratins are also implicated in signaling pathways, inflammation, and disease states. Keratin 9 (KRT9) protein has been identified to have high diagnostic accuracy for Alzheimer’s disease (AD) (PMID:22045497); it was detected in cerebrospinal fluid (CSF) of AD patients but not healthy controls (PMID:24959311). Plasma keratin 9 concentrations also positively correlated with AD‐associated proteins (e.g., apolipoprotein E and tau) in AD patients (PMID:26973255). Post‐translational modification of keratin 83 (KRT83) protein has been associated with serum asymmetric dimethylarginine levels (PMID:34181092), a vascular risk factor implicated in AD. However, our understanding of the role of genetic variation in AD risk is incomplete. Here, we investigate associations between single nucleotide polymorphisms (SNPs) in KRT9, KRT83, and KRT2 (Keratin 2, couples with keratin 9) and AD biomarker phenotypes.MethodIndividuals with mild cognitive impairment (MCI) or AD, and clinically normal controls were selected among ADNI participants. Participants underwent genome‐wide genotyping. Keratin gene variants were identified from the genome‐wide data using dbSNP variant IDs and genotypes were coded additively. Linkage‐disequilibrium‐based clumping on minor allele frequency (MAF) was applied to prioritize more common SNPs. CSF‐Aβ42, ‐tau, and phosphorylated‐tau (p‐tau) levels were quantified via Roche Elecsys immunoassays. Brain‐Aβ deposition was evaluated via normalized PET‐18F‐AV‐45 cortical summary measures (SUVR). White matter hyperintensities (WMH) were obtained from MRI 3D‐T1 and FLAIR sequences via an automated atlas‐based segmentation pipeline. Linear regression models controlling for age, sex, Mini‐Mental State Exam, APOE‐ε4 status, and head size were used to assess association and interaction effects between SNPs and the AD phenotypes in R.ResultAmong included participants (n = 907, 73±7.2 years, 44% female), SNPs in KRT2 (e.g. 3’UTR‐variant rs117041267‐G/A; MAF = 1.4%) and KRT83 (e.g. upstream‐variant KRT83‐rs17119838‐C/T; MAF = 15.6%) were associated with higher CSF‐Aβ42 concentrations (F(2,905) = 4.26,p = 0.014; and F(2,905) = 6.61,p = 0.0014, respectively). Upstream‐variant KRT83‐rs182354391‐C/G (MAF = 1%) showed an association with lower CSF‐tau (F(1,904) = 5.44,p = 0.020). Multiple KRT9 and KRT2 SNPs also showed association with WMH, while KRT2 and KRT83 intron variants showed associations with PET‐Aβ.ConclusionThese candidate gene analyses suggest involvement of multiple keratin family genes in AD, as indicated by differences in amyloid and tau biomarkers, and white matter disease.

DDAH1 Protects against Cardiotoxin-Induced Muscle Injury and Regeneration.

Nitric oxide (NO) is an important biological signaling molecule affecting muscle regeneration. The activity of NO synthase (NOS) is regulated by dimethylarginine dimethylaminohydrolase 1 (DDAH1) through degradation of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). To investigate the role of DDAH1 in muscle injury and regeneration, muscle-specific Ddah1-knockout mice (Ddah1MKO) and their littermates (Ddah1f/f) were used to examine the progress of cardiotoxin (CTX)-induced muscle injury and subsequent muscle regeneration. After CTX injection, Ddah1MKO mice developed more severe muscle injury than Ddah1f/f mice. Muscle regeneration was also delayed in Ddah1MKO mice on Day 5 after CTX injection. These phenomena were associated with higher serum ADMA and LDH levels as well as a great induction of inflammatory response, oxidative stress and cell apoptosis in the gastrocnemius (GA) muscle of Ddah1MKO mice. In the GA muscle of CTX-treated mice, Ddah1 deficiency decreased the protein expression of M-cadherin, myogenin, Bcl-2, peroxiredoxin 3 (PRDX3) and PRDX5, and increased the protein expression of MyoD, TNFα, Il-6, iNOS and Bax. In summary, our data suggest that DDAH1 exerts a protective role in muscle injury and regeneration.

Acute Effects of Online Hemodiafiltration versus High Flux Hemodialysis on Serum Levels of Asymmetric Dimethylarginine (ADMA), and Tumor Necrosis Factor (TNF)-Alpha

Abstract Background In ESRD patients, chronic inflammation is a common feature and results in cardiovascular morbidity and mortality. Aim of the Work to identify a superior merit for convective dialysis over high flux dialysis in decreasing the serum level of tumour necrosis factor alpha (TNF α) and Asymmetric dimethylarginine (ADMA) in ESRD adult population. Patients and Methods This study was conducted on 20 patients from the ESRD patients attending the dialysis unit of nephrology department in Ain Shams specialized hospital, the selected subjects were being treated by dialytic support in the form of two sessions of high flux standard haemodialysis and one session of hemodiafiltration each week. All the selected patients were clinically stable, aged ≥18 years, receiving dialysis for≥ 3 months, with wellfunctioning AV fistulas, not on anti-inflammatory or immunosuppressive drugs for 3 months earlier and during the study. Results there was a highly statistically significant increase in Percent of change (drop) in TNFα post HDF session versus high flux HD session. Similarly, the Percent of change (drop) in ADMA was higher post HDF session versus high flux HD session which represented a highly statistically significant difference. The results of our study showed superiority of HDF over HF HD in TNF α and ADMA clearance. Conclusion Convective clearance plays a crucial role in improving the biomarker profile. Using online hemodiafiltration technique that combines the use of high-flux synthetic membrane with low bio reactive profile and the use of ultrapure dialysis fluid showed a significant reduction of ADMA and TNF alpha in adult with ESRD.

Assessment of serum asymmetric dimethylarginine level in children with beta-thalassemia

Assessment of serum asymmetric dimethylarginine level in children with beta-thalassemia

Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

Efficacy of beetroot juice on reducing blood pressure in hypertensive adults with autosomal dominant polycystic kidney disease (BEET-PKD): study protocol for a double-blind, randomised, placebo-controlled trial

BackgroundIn autosomal dominant polycystic kidney disease (ADPKD) impaired nitric oxide (NO) synthesis, in part, contributes to early-onset hypertension. Beetroot juice (BRJ) reduces blood pressure (BP) by increasing NO-mediated vasodilation. The aim of this double-blind, randomised, placebo-controlled study is to test the hypothesis that BRJ reduces systolic and diastolic clinic BP in hypertensive adults with ADPKD.MethodsParticipants with ADPKD and treated hypertension (n = 60) will be randomly allocated (1:1) to receive a daily dose of either nitrate-replete (400 mg nitrate/day) or nitrate-deplete BRJ for 4 weeks. The co-primary outcomes are change in mean systolic and diastolic clinic BP before and after 4 weeks of treatment with daily BRJ. Secondary outcomes are changes in daily home BP, urinary albumin to creatinine ratio, serum and salivary nitrate/nitrite levels and serum asymmetric dimethylarginine levels before and after 4 weeks of BRJ.DiscussionThe effect of BRJ in ADPKD has not been previously tested. BRJ is an accessible, natural dietary supplement that, if effective, will provide a novel adjunctive approach for treating hypertension in ADPKD.Trial registrationClinicalTrials.gov NCT05401409. Retrospectively registered on 27th May 2022.

Validation of Serum ADMA Levels as a Biomarker for Assessing Cardiovascular Risk in Patients with Coronary Heart Disease: A Study from a Tertiary Care Hospital in Pakistan

Objectives: The diagnostic potential of serum asymmetric dimethylarginine (ADMA) levels as a biomarker for cardiovascular risk has been investigated in various populations, but no such study has been reported in Pakistan. This study aimed to assess the diagnostic efficiency of serum ADMA levels in detecting cardiovascular risk in patients with coronary heart disease (CHD). Methodology: A cross-sectional study was conducted at the Chaudhry Pervaiz Elahi Institute of Cardiology (CPEIC), Wazirabad, Pakistan, using a consecutive sampling technique to ensure randomization. One hundred individuals were divided into two groups (CHD patients and healthy controls), and blood samples were collected between January 2022 and November 2022. Serum ADMA levels were measured using an enzyme-linked immunosorbent assay (ELISA), and statistical analysis was performed to determine the area under the receiver operating characteristic (ROC) curve (AUC). Results: The mean age of CHD patients' serum samples was 58.6 ± 7.39 years (p&lt;0.001) compared to 42.26 ± 14.4 years (p&lt;0.001) in healthy controls. The mean ADMA concentration in the serum of CHD patients was determined as 1.37 ± 0.26 µmol/L (p&lt;0.001) compared to 0.812 ± 0.207 µmol/L (p&lt;0.001) in healthy controls. The AUC on the ROC curve was determined as 0.95, indicating high diagnostic accuracy. ADMA's sensitivity, specificity, and overall accuracy were determined as 82%, 88%, and 85%, respectively. Conclusion: In conclusion, serum ADMA levels demonstrate a promising potential as a biomarker for assessing cardiovascular risk. The findings of this study suggest that ADMA measurements could be utilized as a diagnostic tool in CHD patients, aiding in the identification and management of cardiovascular risk in the Pakistani population. Further research is warranted to validate these findings and explore the utility of ADMA in more extensive and diverse cohorts.

The role of asymmetric dimethylarginine (ADMA) in COVID-19: association with respiratory failure and predictive role for outcome

We aimed to assess the potential role of Asymmetric dimethylarginine (ADMA) in conditioning respiratory function and pulmonary vasoregulation during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Within 72 h from admission, samples from 90 COVID-19 patients were assessed for ADMA, SDMA, L-arginine concentrations. In addition to classical statistics, patients were also clustered by a machine learning approach according to similar features. Multivariable analysis showed that C-reactive protein (OR 1.012), serum ADMA (OR 4.652), white blood cells (OR = 1.118) and SOFA (OR = 1.495) were significantly associated with negative outcomes. Machine learning-based clustering showed three distinct clusters: (1) patients with low severity not requiring invasive mechanical ventilation (IMV), (2) patients with moderate severity and respiratory failure whilst not requiring IMV, and (3) patients with highest severity requiring IMV. Serum ADMA concentration was significantly associated with disease severity and need for IMV although less pulmonary vasodilation was observed by CT scan. High serum levels of ADMA are indicative of high disease severity and requirement of mechanical ventilation. Serum ADMA at the time of hospital admission may therefore help to identify COVID-19 patients at high risk of deterioration and negative outcome.

Asymmetric Dimethylarginine (ADMA) in Cardiovascular Disease, Cardiac Ischemia/reperfusion Injury, and Ischemic Non-obstructive Coronary Artery Disease: Biochemical and Pharmacological Implications

Background: Several studies have shown that high plasma concentrations of asymmetric dimethylarginine (ADMA), a known endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS), correlate with the severity of coronary artery disease (CAD), with worsening of cardiac ischemia/reperfusion (I/R) injury and coronary atherosclerosis. It is believed that it may be an important risk factor for myocardial infarction. ADMA, when in high concentrations, can determine a significant decrease in the synthesis and bioavailability of NO (Nitric oxide) and therefore alter the mechanisms of regulation of coronary vasodilation and vasomotor function of epicardial coronary arteries. Higher serum ADMA concentration is associated with worsening of post-ischemic remodeling since coronary angiogenesis, vasculogenesis, and collateral coronary growth are seriously impaired. In addition, there are reasons to believe that elevated plasma ADMA levels are related to the development of diseases affecting coronary microcirculation, such as ischemic non-obstructive coronary artery disease (INOCA). Methods: Methods: With the aim of providing the pharmacologist engaged in the design and discovery of new ADMA-lowering drugs with a complete examination of the subject, in this review, we discuss the most important studies related to the correlations between serum ADMA levels and cardiovascular diseases mentioned above. In addition, we critically discuss the main aspects of enzymology, synthesis, and metabolism of ADMA as a prerequisite for understanding the molecular mechanisms through which high concentrations of ADMA could contribute to promoting cardiovascular diseases. Results and Conclusion: ADMA represents a new target for pharmacological modulation of cardiovascular endothelial function and therefore, there is a possibility of using selective pharmacological ADMA lowering drugs in cardiovascular disease with endothelial dysfunction and high plasma ADMA levels.

Circadian blood pressure variability and asymmetric dimethylarginine in patients with glaucoma: cross-sectional study of The LIGHT cohort.

Glaucoma is reportedly associated with asymmetric dimethylarginine (ADMA) and circadian blood pressure (BP) variability, including night-time SBP. We determined whether ADMA level is associated with night-time SBP in patients with glaucoma. In this cross-sectional study, we measured the serum ADMA level and ambulatory BP of 163 patients with glaucoma and 705 participants without glaucoma. Based on the tertiles of serum ADMA level, the patients were divided into three groups: low, intermediate, and high-ADMA. Night-time SBP was determined based on ambulatory BP measured every 30 min for 48 h. The nondipper BP pattern was defined as having a night-time mean SBP decline of less than 10% relative to the mean daytime SBP. In the glaucoma group, the night-time SBP in the high-ADMA group was significantly higher than in the low-ADMA group (123.0 and 114.4 mmHg, respectively; P = 0.003). Multivariable analysis adjusted for the potential confounders showed the night-time SBP, and the odds ratio for nondipper in the high-ADMA group were also significantly higher than in the low-ADMA group ( P = 0.030 and P = 0.021, respectively). Significant associations between continuous serum ADMA levels with night-time SBP and nondipper were also found ( P = 0.002 and 0.006, respectively). In the control group, however, no significant associations were found between serum ADMA levels and night-time SBP and nondipper. A significant interaction effect of the serum ADMA levels and glaucoma on nondipper was found ( P = 0.004). Serum ADMA level was significantly associated with the disturbance of circadian BP variability in patients with glaucoma.

Effect of cigarette smoking on serum methylarginine and α-klotho levels

Background and aimsSmoking causes many diseases such as cardiovascular, lung diseases, stroke and premature aging. However, the role of smoking in the pathogenesis of these diseases is unclear. Increasing evidence suggests that methylarginine pathway metabolites and α-klotho may be strong markers for pathologies such as premature aging, endothelial dysfunction, and oxidant damage. Therefore, the study aimed to measure the serum levels of arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), N-monomethyl-l-arginine (L-NMMA), and α-klotho levels in smokers. Methods and resultsThis case-control analytical study included 65 smokers and 71 non-smokers. Sociodemographic characteristics, routine biochemistry parameters, Framingham risk scores and Fagerström Nicotine Dependence Test (FTND) were recorded. Serum methylarginine and α-klotho levels were analyzed by tandem mass spectrometry and enzyme-linked immunosorbent assay (ELISA), respectively. Serum ADMA (p < 0.001), L-NMMA (p = 0.024), SDMA (p < 0.001) levels of smokers were higher than non-smokers, and serum α-klotho (p < 0.001) and arginine levels (p < 0.001) were lower. There was a positive correlation between serum ADMA levels with FNDT, age and pack/year in smokers, while there was a negative correlation between klotho levels and age. A positive correlation was found between serum ADMA levels, Framingham risk score and age in non-smokers. ConclusionSmoking is related to premature aging and is a strong risk factor for various diseases such as cardiovascular, inflammatory, and renal diseases. Elevated serum methylarginine and decreased serum klotho levels were found in smokers. Therefore, our findings suggest that smoking may be involved in the pathogenesis of these diseases by affecting α-klotho and methylarginine-related pathways.

The effects of proton pump inhibitors on the development of post-stenting major adverse cardiovascular events in patients with acute coronary syndrome

Proton pump inhibitors (PPIs) are recommended for the prevention of gastrointestinal bleeding in acute coronary syndrome (ACS) patients who receive dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) but have been associated with an increased risk of major adverse cardiovascular events (MACE) in these patients. We aimed to investigate the relationship between serum asymmetric dimethylarginine (ADMA) and copeptin levels and MACE in those who started on imminent DAPT and PPI therapy after PCI. 90 patients with ACS were included in this prospective observational study and divided into three groups lansoprazole (n=30), rabeprazole (n=31), and pantoprazole (n=29). The serum ADMA and copeptin levels were examined at the time of diagnosis, at the end of 1st and 6th month. MACE was defined as mortality, recurrent AMI (acute myocardial infarction), and CST (coronary stent thrombosis) development after PCI. MACE developed in two patients in the first month and eight patients (8.9%) after six months of follow-up. At six months, CST was seen in only two patients (2.2%). At the first-month evaluation, while a significant increase was observed in serum ADMA levels at the time of admission (p&lt;0.001), the copeptin levels decreased significantly in all patients (p&lt;0.001). In the 6th month, the serum ADMA and copeptin levels significantly increased compared to the time of admission and 1st-month evaluation in all groups (p&lt;0.001). PPIs might significantly influence serum ADMA and copeptin levels in patients undergoing coronary stenting due to ACS. Nevertheless, we did not notice clinical extrapolation of the potential effects.

Acute effects of online hemodiafiltration versus high-flux hemodialysis on serum levels of asymmetric dimethylarginine and tumor necrosis factor-alpha

Background Chronic inflammation as a major determinant of ‘dialysis syndrome’ is considered as the main factor of morbidity and mortality in dialysis patients. Tumor necrosis factor-alpha (TNF-α) may play important roles in the development of T helper (Th) imbalance, cardiovascular disease, and wasting in the uremic milieu. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide that may be an independent risk factor for endothelial dysfunction and cardiovascular disease. In hemodialysis (HD) patients, plasma ADMA is a strong and independent predictor of overall mortality and cardiovascular outcome. The aim of this study to evaluate the acute effects of hemodiafiltration (HDF) compared with conventional HD on blood levels of ADMA and TNF-α. Patients and methods A cross-sectional study was conducted on 20 patients with end-stage renal disease receiving dialysis in the dialysis unit of Ain Shams Specialized Hospital receiving twice weekly HD session with high-flux (HF) dialyzer and once weekly HDF session. Blood samples were collected from all participants before and after HD session and from the same participants before and after HDF session. ADMA and TNF-α levels were assessed by enzyme-linked immunosorbent assay techniques. Results The decrease in TNF-α was higher after HDF session versus HF HD session (79.47 ± 14.16 vs. 50.43 ± 31.05), with P value of 0.001. Moreover, the decrease in ADMA was higher after HDF session versus HF HD session (75.01 ± 12.55 vs. 41.79 ± 24.73), with P value of 0.001. Conclusion The use of online HDF technique showed a significant reduction of ADMA and TNF-α in adults with end-stage renal disease.

Asymmetric dimethylarginine correlates with worsening peripheral microangiopathy in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized primarily by micro-angiopathy and endothelial dysfunction which stimulate a fibrotic process. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor and represents a novel biomarker for vascular dysfunction. Nailfold video capillaroscopy (NVC) represents a non-invasive and reliable technique for the evaluation of microvasculopathy in SSc. The aim of this study was to examine the possible association between ADMA and microvascular involvement in patients with SSc. This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA was measured in serum samples using a commercial enzyme immunoassay. Participants underwent NVC with qualitative and semi-quantitative assessment and all NVC parameters were measured in the distal row of each finger. The findings were classified in one of the three qualitative NVC patterns: early, active, and late. Eighty-one (92,6% women) SSc individuals with mean age 55.44±13.4years were included in this analysis. Within-groups comparisons revealed a trend between higher ADMA levels and progressive micro-vasculopathy (1,29 [2,1] vs 1,57 [1,95] vs 2,41 [3,87]; for early, active and late patterns respectively, p=0.039). Furthermore, ADMA concentration was significantly associated with the number of capillaries/mm (r=-0.235; p=0.035). Serum ADMA levels were significantly associated with advancing stages of microcirculatory abnormalities suggesting that ADMA may have a role in promoting microvascular endothelial dysfunction in SSc individuals.

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis.

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.

The effect of haptoglobin genotype on the association of asymmetric dimethylarginine and DDAH 1 polymorphism with diabetic macroangiopathy

BackgroundDimethylarginine dimethylaminohydrolase (DDAH) 1 maintains the bioavailability of nitric oxide by degrading asymmetric dimethylarginine (ADMA). Here, we aimed to investigate the effect of haptoglobin (Hp) genotype on the association of ADMA and DDAH 1 polymorphism with diabetic macroangiopathy.MethodsIn stage 1, 90 Chinese participants with type 2 diabetes were enrolled to measure a panel of targeted metabolites, including ADMA, using tandem mass spectrometry (BIOCRATES AbsoluteIDQ™ p180 kit). In stage 2, an independent cohort of 2965 Chinese patients with type 2 diabetes was recruited to analyze the effect of Hp genotype on the association between DDAH 1 rs233109 and diabetic macroangiopathy. Hp genotypes were detected using a validated assay based on the TaqMan method. DDAH 1 rs233109 was genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using the MassARRAY platform.ResultsIn stage 1, serum ADMA levels correlated with common Hp genotypes (β ± SE = − 0.049 ± 0.023, P = 0.035), but not with diabetic macroangiopathy (P = 0.316). In stage 2, the distribution of DDAH 1 rs233109 genotype frequencies was 15% (CC), 47% (TC), and 38% (TT), which was in Hardy-Weinberg equilibrium (P = 0.948). A significant Hp genotype by rs 233109 genotype interaction effect on diabetic macroangiopathy was found (P = 0.017). After adjusting for confounders, patients homozygous for rs233109 CC were more likely to develop diabetic macroangiopathy than those carrying TT homozygotes in the Hp 2-2 subgroup [odds ratio = 1.750 (95% confidence interval, 1.101–2.783), P = 0.018].ConclusionHp genotype affects the association between DDAH 1 rs233109 and diabetic macroangiopathy in Chinese patients with type 2 diabetes.

The ADMA–DDAH1 axis in ovarian apoptosis of polycystic ovary syndrome

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) mainly degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. Emerging evidence suggested that plasma ADMA is accumulated in patients with polycystic ovary syndrome (PCOS). However, ADMA–DDAH1 involvement in PCOS pathogenesis is unclear. Here, we used dehydroepiandrosterone (DHEA)-induced PCOS rats and the ovarian granulosa cell line KGN to investigate the effect of the ADMA–DDAH1 pathway on ovarian apoptosis. Moreover, we also quantified the ADMA levels and redox status in human serum specimens, Sprague Dawley rats and KGN cells to investigate the effect of ADMA–DDAH1 on redox status and ovarian apoptosis in PCOS. We enrolled 19 women with PCOS and 17 healthy women (controls) in this study. The women with PCOS had increased serum ADMA levels and decreased glutathione peroxidase (GSH-PX) compared with the controls. In Sprague Dawley rats, 21-day DHEA treatment established PCOS and the rat contained higher ADMA levels in serum and lower DDAH1 expression in ovaries. Moreover, the PCOS rat serum and ovaries exhibited increased levels of the oxidative stress marker malondialdehyde (MDA). ADMA treatment of the KGN cells induced reactive oxygen species accumulation and led to apoptosis. Contrastingly, overexpressing DDAH1 in the KGN cells significantly decreased ADMA levels, enhanced cell viability, and inhibited oxidative stress, while the effect was inverse in DDAH1 knockdown cells. Overall, our results demonstrated that PCOS involves elevated ADMA levels and redox imbalance. The ADMA–DDAH1 pathway exerted a marked effect on oxidative stress and ovarian apoptosis in PCOS. Our findings suggested that strategies for increasing DDAH1 activity in ovarian cells may provide a novel approach for ameliorating PCOS.

Raised total methylated arginine load in patients with gout.

Aim: The aim of this study was to measure serum levels of methylarginine derivatives and related metabolites in patients with gout. Materials & methods: This study enrolled 100 patients with gout and 80 patients in the control group. Serum asymmetric dimethylarginine, symmetric dimethylarginine, L-N-monomethylarginine, arginine, homoarginine, citrulline and ornithine levels were measured with tandem mass spectrometry. Results: Serum ornithine, citrulline and total methylated arginine load levels were statistically significantly higher in patients with gout compared with the control group, while serum arginine and homoarginine levels and global arginine bioavailability ratio were statistically significantly lower. Conclusion: There may be an association between gout, methylarginine levels and hyperuricemia and increased risk of cardiovascular disease.