Increased Asymmetric Dimethylarginine Levels Research Articles

Pan-methylarginine antibody generation using PEG linked GAR motifs as antigens.

Arginine methylation is a prevalent posttranslational modification which is deposited by a family of protein arginine methyltransferases (PRMTs), and is found in three different forms in mammalian cells: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Pan-methylarginine antibodies are critical for identifying proteins that are methylated on arginine residues, and are also used for evaluating signaling pathways that modulate this methyltransferase activity. Although good pan-MMA, -ADMA and -SDMA antibodies have been developed over the years, there is still room for improvement. Here we use a novel antigen approach, which involves the separation of short methylated motifs with inert polyethylene glycol (PEG) linkers, to generate a set of pan antibodies to the full range of methylarginine marks. Using these antibodies, we observed substrate scavenging by PRMT1, when PRMT5 activity is blocked. Specifically, we find that the splicing factor SmD1 displays increased ADMA levels upon PRMT5 inhibitor treatment. Furthermore, when the catalysis of both SDMA and ADMA is blocked with small molecule inhibitors, we demonstrate that SmD1 and SMN no longer interact. This could partially explain the synergistic effect of PRMT5 and type I PRMT inhibition on RNA splicing and cancer cell growth.

Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation

Mechanical force is critical for the development and remodeling of bone. Here we report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine (ADMA) via regulating the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 (Ddah1) expression in osteoblasts. The presence of -394 4 N del/ins polymorphism of Ddah1 and higher serum ADMA concentration are negatively associated with bone mineral density. Global or osteoblast-specific deletion of Ddah1 leads to increased ADMA level but reduced bone formation. Further molecular study unveils that mechanical stimulation enhances TAZ/SMAD4-induced Ddah1 transcription. Deletion of Ddah1 in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. Taken together, the study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation.

Plasma Asymmetrıc Dımethylargınıne (ADMA) and Nıtrıc Oxıde (NO) Levels ın Patıents wıth Chronıc Pansınusıtıs.

Chronic pansinusitis is a mucosal inflammation of the nose and all paranasal sinuses with severe inflammation of the upper airways. Asymmetric dimethylarginine (ADMA) is associated with oxidative stress. In this study, we aimed to examine the plasma levels and importance of ADMA and nitric oxide (NO) in patients with chronic pansinusitis. The study was conducted with a total of 64 patients. The study group included a total of 40 patients with chronic pansinusitis. (18females, 22males) (mean age 32.27 ± 10.02). The control group consisted of 24 patients (11 females and 13 males). The mean age of the patients in the control group was 31.35 ± 6.05years. Nasal endoscopic examinations were performed in patients with a history of chronic pansinusitis and symptoms of chronic pansinusitis. Later, the diagnosis of chronic pansinusitis was confirmed with coronal paranasal sinus Computed tomography scans. Plasma ADMA levels were measured by ELISA method and NO levels were measured by Griess method. Plasma ADMA and NO levels of the patients and healthy volunteers were measured and the mean plasma levels of the two groups were compared. ADMA levels were significantly higher in the group with chronic pansinusitis compared to the control group (1.23 ± 0.41μM and 0.28 ± 0.06μM, respectively) (p < 0.001), while NO levels were significantly lower in the patient group compared to the control group (7.06 ± 1.07μM and 12.25 ± 0.95, μM, respectively) (p < 0.001). Our results show that the increase in ADMA levels and the decrease in NO levels are associated with chronic pansinusitis. According to these results, increased plasma levels of ADMA in chronic pansinusitis may be useful in clinical use as a sign of increased oxidative stress.

DDAH-1, via regulation of ADMA levels, protects against ischemia-induced blood-brain barrier leakage

Dimethylarginine dimethylamino hydrolase-1 (DDAH-1) is an important regulator of nitric oxide (NO) metabolism that has been implicated in the pathogenesis of cardiovascular diseases. Nevertheless, its role in cerebral ischemia still needs to be elucidated. Herein, we examined the expression of DDAH-1 in the brain of rat by double-label immunofluorescence staining. DDAH-1 knock-out (DDAH-1−/−) and wild-type rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, neurological scores, TTC staining and TUNEL assay were used to evaluate neurological damages. 3 and 7-days infarct outcomes were also shown. Blood-brain-barrier (BBB) permeability was examined via Evans blue extravasation and tight junction (TJ) proteins expression and mRNA levels by western blot and RT-qPCR. The levels of plasma asymmetric dimethylarginine (ADMA), NO and ADMA in brain tissue were also assessed. In addition, supplementation of L-arginine to DDAH-1−/− rats was used to explore its role in regulating NO. DDAH-1 was abundantly distributed in cerebral cortex and basal nuclei, and mainly expressed in neurons and endothelial cells. DDAH-1−/− rats showed aggravated neurological damage and BBB disruption, including decrease of TJ proteins expression but indistinguishable mRNA levels after MCAO/R. DDAH-1 depletion and neurological damages were accompanied with increased ADMA levels and decreased NO concentrations. The supplementation with L-arginine partly restored the neurological damages and BBB disruption. To sum up, DDAH-1 revealed to have a protective role in ischemia stroke (IS) and IS-induced leakage of BBB via decreasing ADMA level and possibly via preventing TJ proteins degradation.Dimethylarginine dimethylamino hydrolase-1 (DDAH-1), as the critical enzyme responsible for asymmetric dimethylarginine (ADMA) degradation, serves as a protective factor for ischemic stroke. DDAH-1 protects ischemia-induced disruption of blood-brain-barrier via regulating ADMA level and preventing tight junction proteins degradation. The supplementation of L-arginine helps restore the function of DDAH-1.

Changes in the asymmetric dimethylarginine and endothelial nitric oxide synthase levels in pathogenesis of experimental diabetic retinopathy

Endothelial dysfunction associated with impaired nitric oxide excretion plays an important role in the onset and progression of diabetic retinopathy. It has been proven that a decrease in the activity of endothelial NO-synthase (еNО-S), the inhibitor of which is asymmetric dimethylarginine (ADMA), plays an important role in this. Objective: to study the level of asymmetric dimethylarginine and endothelial nitric oxide synthase at different stages of development of diabetic retinopathy in the experiment. The study was conducted in Wistar white rats of 180-200 g weight. According to the tasks, the animals were separated into 2 groups as follows: group 1 – 60 intact animals, group 2 – 60 animals with simulated diabetic retinopathy without further correction. Type 2 diabetes mellitus and diabetic retinopathy were simulated through intraperitoneal administration of Streptozotocin (Sigma, USA) diluted in 0.1M citrate buffer with pH=4.5. Streptozotocin dose of 55 mg per kg of animal weight was divided into two administrations. The streptozotocin intake was preceded by a 28-day high-fat diet. Our study showed impaired endothelial function in diabetic retinopathy, as evidenced by an increased ADMA level (p&lt;0.001). We have determined a stepwise increase of asymmetric dimethylarginine level in blood of rats with simulated pathology which is apparent in its highest at phase 3. Pathogenetic effect of increased ADMA on еNО-S activity was verified at all experimental stages, Impairment of physiological nitric oxide synthesis in simulated pathology has been proved as evidenced by reduced activity of endothelial NO-synthase yet on the 30th day with further negative dynamics up to the 180th day (p&lt;0.001 compared with the intact group findings).

ST Segment Yükselmeli Miyokardial Enfarktüs İle Başvuran Hastalarda Asimetrik Dimetilarjinin Düzeyinin Kisa Ve Uzun Dönem Prognoz İle İlişkisi

objecitves: ST segment elevation myocardial infarction (STEMI) is regarded as a type of acute coronary syndrome. However, the mortality of STEMI patients is substantial. Asymmetric dimethylarginine (ADMA) is the major inhibitor of nitric oxide biosynthesis in humans. Studies have shown that increased ADMA levels are associated with endothelial dysfunction and increased atherogenesis. It is aimed to show the relationship between ADMA and prognosis of ST elevation MI. Materials and methods: The study population was 45 (40 male, 5 female) patients with diagnosis of STEMI, who underwent primary percutaneous coronary intervention (PCI). Demographic data, blood tests and medical history of the patients were recorded. Ten cc of blood samples were collected right after sheat application. ADMA levels were studied by ELISA kit. Results: The follow-up period was 42.837±14.343 months. The mean age was 52.4±7.8. Only significant relation was observed between ADMA levels and heart rate (p=0.025). Other relations with demographic data, risk factors for STEMI, follow-up events such as major adverse cardiovascular events, heart failure, target vessel revascularization, reinfarction, ongoing myocardial ischemia, in-hospital events, intervention artery, type of intervention, Pre-TIMI, ejection fraction, use of tirobufan, anterior or inferior MI were not statistically significant (p>0.05). Although, a positive relation was observed between ADMA levels and chronic heart failure, it was not significant. Conclusions: Although, there was a relation with heart failure, the only significant relation was found between ADMA levels and heart rate. Further studies with greater number of participants should be performed for drawing strict conclusions.

Serum asymmetric dimethylarginine, a novel risk marker of coronary artery disease

Coronary artery disease (CAD) is a chronic disease and a global health problem, affecting one-third of the world’s population. Recently it has been found that the traditional risk factors of CAD do not account for the total risk. One of the novel risk markers of CAD is Asymmetric dimethylarginine (ADMA), which inhibits the enzyme nitric oxide synthase (NOS), which is required for the synthesis of nitric oxide (NO), a potent vasodilator. Increased ADMA level causes decrease in NO level which will lead to endothelial dysfunction, an underlying causative mechanism for CAD development. ADMA is found to be an independent cardiovascular risk factor. Therefore ADMA may become an additional biochemical parameter to identify those patients who are at higher risk for developing CAD, besides the traditional parameters used.To study the association between serum ADMA level with coronary artery disease.The study design is a case-control study. 80 subjects from the south Indian population between 30 to 60 years of age, of both the sexes were included in the study. Out of them, 40 individuals were angiographically proven cases of CAD from the department of cardiology and 40 healthy individuals from the master health check up department. Various parameters like lipid profile, serum ADMA, blood pressure and BMI were measured in both the groups. The data were collected and analyzed.The ADMA level was found to be significantly elevated in the case group compared with the age matched healthy controls (p value &amp;#60; 0.05).There is a positive correlation between serum ADMA level and coronary artery disease.

Meme Kanseri Olan Hastalarda Serum Homoarjinin ve İskemi Modifiye Albumin Düzeyleri

Objectives: Homoarginine and ischemia modified albumin are among the molecules that are intensely studied on. Homarginine and ischemia-modified albumin levels in breast cancer patients are extremely important in understanding the pathogenesis of diseases, associating these molecules with treatment, developing new treatment protocols, and even eliminating risk factors in healthy people before diseases occur. Our aim in this study is to determine homoarginin and ischemia-modified albumin levels in the serum of breast cancer patients and its relation with the disease. Material and Methods: 27 controls, 27 breast cancer were included in the study. Serum methylarginine and homoarginine levels were studied by mass spectrometric method, and ischemia modified albumin levels by colorimetric method in Selcuk University Faculty of Medicine Biochemistry Laboratory. Results: While the levels of L-monomethylarginine, Total Methyl Arginine, Homoarginine statistically decreased, asymmetric dimethylarginine and ischemia modified albumin levels significantly increased in patients compared to controls (p &lt;0.05). Conclusions: Increased ischemia modified albumin levels may indicate the oxidative stress that occurs in breast cancer. Increase in asymmetric dimethylarginine levels can lead to decreased nitric oxide synthesis and deterioration of the vascular structure. Keywords: Breast cancer; Homoarginine; Ischemia modified albumin; Mass spectrometry

Effects of Aerobic Exercise Induced Metabolic and Cardiac Stress on Irisin Levels in Trained Subjects

Objective: Exercise is known to be accelerates metabolic activity and increases oxidative stress levels of the body. Irisin is an exercise induced myokine which plays crucial role in energy regulation and oxidative stress. We aimed to evaluate effects of aerobic exercise induced cardiac and skeletal muscle stress as determined on malondialdehyde (MDA) and asymmetric dimethylarginine (ADMA) ADMA on irisin levels in trained male subjects. Material and Methods: Total of 25 male performed aerobic running exercise corresponded to their anaerobic threshold levels approximately 45 min. Venous blood samples were taken before and immediately after exercise. Serum irisin levels were determined using enzyme-linked immunoassay (ELISA) method. ADMA and MDA measured by using high performance liquid chromatography (HPLC). Results: Aerobic exercise led to systematic increase in ADMA (0.417±0.05 µmol/L vs 0.537±0.05 µmol/L), MDA (0.769±0.02 µmol/L vs 1.012±0.04 µmol/L) and irisin (252±4 ng/ml vs 299±4 ng/ml). In addition, we have observed significant correlation between increased ADMA and irisin levels during exercise Conclusion: We observed close relationships between exercises induced cardiac muscle stress as determined from increased ADMA levels and increased irisin levels. Thus, irisin may be considered as a protective agent for the patients with cardiovascular system impairments.

Protein Arginine Methyltransferases in Cardiovascular and Neuronal Function.

The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a type of post-translational modification which is important for numerous cellular processes, including mRNA splicing, DNA repair, signal transduction, protein interaction, and transport. PRMTs have been extensively associated with various pathologies, including cancer, inflammation, and immunity response. However, the role of PRMTs has not been well described in vascular and neurological function. Aberrant expression of PRMTs can alter its metabolic products, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). Increased ADMA levels are recognized as an independent risk factor for cardiovascular disease and mortality. Recent studies have provided considerable advances in the development of small-molecule inhibitors of PRMTs to study their function under normal and pathological states. In this review, we aim to elucidate the particular roles of PRMTs in vascular and neuronal function as a potential target for cardiovascular and neurological diseases.

Role of Asymmetric Dimethylarginine and Nitric Oxide in Type 2 Diabetes Mellitus and Its Cardiovascular Complications

AN ENDOGENOUS inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (T2DM) and has been related to atherosclerotic disease. The study aims at investigating the status of ADMA and nitric oxide (NO) and their possible correlation inpatients with T2DM with and without cardiovascular complicationsin comparison to normalcontrols. Forty patients with T2DM and 20 age, sex and body mass index (BMI)‑matched healthy controls were included in the study. The studied individuals were divided into Group1: healthy controls (n= 20), Group 2: T2DM patients without cardiovascular complications (n= 20) and Group 3: T2DM patients with evidence of cardiovascular complications (n= 20). Serum ADMA levels were determined by enzyme linked Immunosorbent Assay (ELISA). Serum nitric oxide was measured as stable end product, nitrite. Insulin was measured by immunoradiometric method. Serum ADMA levels showed a significant elevation while serum NO levels were significantly reducedin diabetic patients groups in comparison to controls. Diabetic patients with vascular complications showed highly significant increase in ADMA levels and pronounced decrease in NO compared to those without complications. In the group of vascular complications, the ADMA level was positively correlated with postprandial serum glucose and HbA1c, but there was a negative correlation between ADMA levels and NO. ADMA and NO may serve as predictors for future cardiovascular events in T2DM patients. Further studies are required to establish the utility of decreasing ADMA levels or increasing NO in the management of T2DM patients.

The clinical effects of l-arginine and asymmetric dimethylarginine: implications for treatment in secondary Raynaud's phenomenon.

Secondary Raynaud's phenomenon (RP) is often the sentinel clinical finding in systemic sclerosis and may precede systemic disease by several years. Altered nitric oxide metabolism plays a critical role in both fibrosis and severe secondary RP phenotypes in these patients. Increased flux through inducible nitric oxide synthase (iNOS) drives cutaneous fibrosis. Failure of flux through endothelial nitric oxide synthase (eNOS) contributes to increased vasoconstriction and decreased vasorelaxation. The underproduction of nitric oxide by eNOS is in part due to increased levels of asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase. The inhibitory effects of increased ADMA levels may be counteracted increasing serum l‐arginine, which is often an effective treatment strategy in these patients. As such, l‐arginine‐based therapies should be considered in managing secondary RP, particularly given their favourable safety and tolerability profile. While there is no established dosing regimen, studies of oral l‐arginine in secondary RP suggest that divided dosing may begin at 1–2 g/day and may be titrated up to 10 g/day. Conversely, primary RP is not associated with increased ADMA production which likely accounts for the failure of l‐arginine trials to show benefit in primary RP.

Changes of oxidative stress markers after treatment of diabetic neuropathy with alpha-lipoic acid

Aim: Diabetic neuropathy has emerged as one of the most common diabetic complications and increased oxidative stress has been related to the progression of diabetic neuropathy. Paraoxonase (PON1) may have an important role in decreasing oxidative stress. Asymmetric dimethylarginine (ADMA), represents a risk factor for the endothelial dysfunction and studies have indicated substantial interaction between oxidative stress and increased ADMA levels.

DIFFERENCES OF ASYMMETRIC DIMETHYL ARGININE LEVEL IN PATIENTS WITH DIABETIC NEPHROPATHY AND NON-DIABETIC NEPHROPATHY

Endothelial dysfunction occurs early in Diabetic Nephropathy (DN), characterized by elevated Asymmetric Dimethylarginine (ADMA) levels. Increased ADMA levels may inhibit endothelial Nitric Oxide Synthase (eNOS) production which are required for Nitric Oxide (NO) formation. Decreased NO levels can increase peripheral resistance and exacerbate the endothelial dysfunction. By knowing the difference of ADMA levels in DN and non-DN patients can help the follow-up and management for the progression of endothelial dysfunction. The purpose of this research was to know the difference of ADMA levels in DN and non-DN by a cross-sectional observational analytical method in 53 diabetes mellitus patients at the Dr. Hasan Sadikin Hospital Bandung (December 2016-July 2017). Urine samples were examined to calculate urinary creatinine albumin ratio (uACR) and serum for ADMA levels. Asymetric dimethylarginin was examined by micro ELISA. Most of the subjects were males (60.38%) with the highest age in the range of 55-64 years (45.28%). Increased ADMA levels were found in 100% of DN and 18.5% of non-DN. Median ADMA levels were found in DN 1.01(0.73-2.25) µmol/L and non-DN 0.57(0.27-1.17) µmol/L, showing a significant difference of ADMA levels (p&lt;0.001). High ADMA levels showed endothelial dysfunction in DN. Serum ADMA levels in DN patients were higher than in non-DN.

Effects of Theobroma cacao on heat shock protein 90 and asymmetric dimethylarginine of endothelial cells under the influence of plasma of pre-eclamptic patients

ObjectivesThis study was conducted to investigate the modulatory role of an ethanol extract of Theobroma cacao beans on heat shock protein 90 (HSP90) and asymmetric dimethylarginine (ADMA) levels of endothelial cells under the influence of plasma of pre-eclamptic patients.MethodsThe endothelial cells were obtained from a human umbilicus. In the confluent phase, the cells were subdivided into groups: the control group (no treatment), the endothelial cell group that was exposed to 2% pre-eclamptic patients' plasma, and the endothelial cell group that was exposed to 2% pre-eclamptic patients' plasma and treated with the ethanol extract of T. cacao at various doses (25, 50, or 100 ppm). Analysis of HSP90 levels was carried out by an enzyme-linked immunosorbent assay. Quantification of ADMA was conducted by immunocytochemistry.ResultsThere was a decreased HSP90 level in the group exposed to the pre-eclamptic patients' plasma. This decrease was significantly attenuated by the extract of T. cacao at the doses of 50 and 100 ppm. The pre-eclamptic patients' plasma significantly increased ADMA level as compared with the control group. This increase was significantly attenuated by the administration of the T. cacao extract at the two highest doses.ConclusionsThe extract of T. cacao beans protected the endothelial cells that were exposed to pre-eclamptic patients' plasma by increasing HSP90 levels and reducing ADMA levels.

1026 GENDER DIFFERENCES IN THE ASSOCIATION BETWEEN SERUM ASYMMETRIC DIMETHYLARGININE, CHRONIC KIDNEY DISEASE, AND QUALITY OF OBJECTIVE/SUBJECTIVE SLEEP: THE HEIJO-KYO COHORT

Sleep problems are common in individuals with chronic kidney disease (CKD), although the underlying mechanisms are largely unknown. Nitric oxide (NO) plays an important role in regulating physiological process in sleep/wake states; however, the association between serum asymmetric dimethylarginine (ADMA) level, an endogenous competitive inhibitor of NO synthesis, and sleep quality has not been studied yet. We measured serum ADMA level along with actigraphic and subjective sleep quality among 1115 elderly individuals with and without CKD (mean age, 71.9 years). Multivariable analysis adjusted for age, BMI, hypertension, diabetes, and physical activity revealed that, in females, compared with the low-ADMA/non-CKD groups (n = 312), sleep efficiency (SE) was significantly lower in the high-ADMA/CKD (n = 52) by 3.5% for objective (95% CI, 1.1–5.9; P = 0.005) and 4.2% (95% CI, 0.3–8.0; P = 0.034) for subjective but not in the low-ADMA/non-CKD group (n = 179) and the high-ADMA/CKD group (n = 36). In males, no significant associations between ADMA and sleep quality were observed. Consistently, the high-ADMA/CKD group exhibited significantly longer wake after sleep onset by 11.3 min (95% CI, 3.0–19.6; P = 0.008) for objective and 25.9 min (95% CI, 4.9–46.9; P = 0.016) for subjective than that in low-ADMA/non-CKD group in females but not in males. No significant association of ADMA and sleep onset latency was observed in both genders. Elderly individuals with high ADMA and CKD exhibited poor sleep quality measured objectively and subjectively than those with low ADMA and without CKD. In addition, potential gender differences in the associations were detected in this study. Increased ADMA levels in CKD may be a possible mechanism underlying high prevalence of sleep problems in CKD patients.

Asymmetric Dimethylarginine in Patients with Ascending Aortic Aneurysms.

Ascending thoracic aortic aneurysm (aTAA) is a heterogeneous group of disorders that involve impaired endothelial function. The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) serves as an endothelial dysfunction marker. Thus, we investigated ADMA levels in patients with aTAA. Eighty-six patients with aTAA and 18 healthy individuals were enrolled. All patients underwent echocardiography. Plasma ADMA levels were measured using high-performance liquid chromatography. ADMA levels were higher in aTAA patients than in control patients (p = 0.034). According to the multivariable regression model, higher ADMA levels were associated with ascending aortic diameter (p = 0.017), smoking (p = 0.016), and log-transformed estimated glomerular filtration rate (eGFR, p = 0.005). This pilot study demonstrates an association of ADMA with ascending aortic dilatation; however, further studies are needed to investigate whether increased ADMA levels underlie aTAA development.

Hyper-activation of pp60Src limits nitric oxide signaling by increasing asymmetric dimethylarginine levels during acute lung injury

The molecular mechanisms by which the endothelial barrier becomes compromised during lipopolysaccharide (LPS) mediated acute lung injury (ALI) are still unresolved. We have previously reported that the disruption of the endothelial barrier is due, at least in part, to the uncoupling of endothelial nitric oxide synthase (eNOS) and increased peroxynitrite-mediated nitration of RhoA. The purpose of this study was to elucidate the molecular mechanisms by which LPS induces eNOS uncoupling during ALI. Exposure of pulmonary endothelial cells (PAEC) to LPS increased pp60Src activity and this correlated with an increase in nitric oxide (NO) production, but also an increase in NOS derived superoxide, peroxynitrite formation and 3-nitrotyrosine (3-NT) levels. These effects could be simulated by the over-expression of a constitutively active pp60Src (Y527FSrc) mutant and attenuated by over-expression of dominant negative pp60Src mutant or reducing pp60Src expression. LPS induces both RhoA nitration and endothelial barrier disruption and these events were attenuated when pp60Src expression was reduced. Endothelial NOS uncoupling correlated with an increase in the levels of asymmetric dimethylarginine (ADMA) in both LPS exposed and Y527FSrc over-expressing PAEC. The effects in PAEC were also recapitulated when we transiently over-expressed Y527FSrc in the mouse lung. Finally, we found that the pp60-Src-mediated decrease in DDAH activity was mediated by the phosphorylation of DDAH II at Y207 and that a Y207F mutant DDAH II was resistant to pp60Src-mediated inhibition. We conclude that pp60Src can directly inhibit DDAH II and this is involved in the increased ADMA levels that enhance eNOS uncoupling during the development of ALI.

Asymmetric Dimethylarginine correlates significantly with tumour necrosis alfa but not with brachial ankle pulse wave velocity in the T2DM-METS

Background: Endothelial dysfunction is an important phenomenon in the pathogenesis of atherosclerosis and is related to the derangements of nitric oxide (NO) synthase in the vessel wall. Asymmetric Dimethylarginine (ADMA) is an endogenous, competitive inhibitor of nitric oxide synthase and is induced by inflammatory cytokines of tumour necrosis factor (TNF)-a in vitro. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilatation. There is cause and effect relationship between endothelial dysfunction and vascular stiffening. Measurement of brachial ankle pulse wave velocity (baPWV) is simple and applicable for cardiovascular risk screening and as a marker for the severity of atherosclerotic vascular damage. Aim: To investigate the correlation between ADMA level with TNF-a and baPWV in the type-2 diabetes mellitus (T2DM)-Metabolic Syndrome (Mets) patients. Method: This is a cross sectional study with T2DM-Mets patients who came to the outpatient clinic of Soetomo Hospital Surabaya during January 2010 to December 2012. Subjects met the inclusion and exclusion criteria were measured their ADMA, TNF-a, and blood glucose levels in plasma. Brachial ankle pulse wave velocity (ba-PWV) was determined by using the V Serra-1000. The study was approved by the local Research Ethics Committee and subjects gave written informed consent. Results: Thirty-seven T2DM-Mets patients consisted of 15 (40.5%) males and 22 (59.5%) females who met inclusion and exclusion criteria were enrolled in this study. Their mean of age was 51 ± 5.2 years old, duration of illness was 16.49 ± 23.4 months, A1C level was 8.5 ± 0.9%, BMI was 26.7 ± 4.5 kg/m2, ADMA level was 0.572 ± 0.2 μmol/L, TNF-a level was 10.0 ± 16.5 pg/mL, and ba-PWV was 1,624.5 ± 295.5 cm/s. Spearman’s correlation analysis showed that ADMA level was significantly correlated with TNF-a level (p = 0.026; r = 0.366). However, no significant correlation found with ba-PWV (p = 0.134; r = 0.251). Conclusion: ADMA level is correlated with TNF-a level in this T2DM-MetS population.

Postnatal high-fat diet leads to spatial deficit, obesity, and central and peripheral inflammation in prenatal dexamethasone adult offspring rats.

Synthetic glucocorticoids are frequently used in clinical practice for treating pregnant women at risk of preterm delivery, but their long-term effects on the infant brain are largely unknown. Pregnant Sprague-Dawley rats were administered vehicle or dexamethasone between gestational days 14 and 21. Male offspring were then weaned onto either a standard chow or a high-fat diet. The postnatal levels of insulin-like growth factor I (IGF-1), tumor necrosis factor-α (TNF-α), and asymmetric dimethylarginine (ADMA) in the plasma, liver, and brain were examined, as well as the possible effects of prenatal dexamethasone on cognition. We found that a postnatal high-fat diet led to spatial deficits detected by the Morris water maze in adult offspring administered dexamethasone prenatally. The spatial deficit was accompanied by decreased IGF-1 mRNA and increased ADMA levels in the dorsal hippocampus. In peripheral systems, a postnatal high-fat diet resulted in decreased plasma IGF-1, increased plasma corticosterone, increased concentrations of transaminases, TNF-α mRNA, and ADMA in the liver, and associated obesity in adult offspring administered prenatal dexamethasone. In conclusion, a postnatal high-fat diet led to spatial deficits, obesity, and altered levels of IGF-1, TNF-α, and ADMA in the plasma, liver, or brain.