Role Of Asymmetric Dimethylarginine Research Articles

Role of asymmetric dimethylarginine in rheumatological disease's cardiovascular complications

Inflammation that is an independent predictor of cardiovascular disease plays a important role in rheumatological diseases. Asymmetric dimethylarginine (ADMA), an inhibitor of endogenous nitric oxide synthase, contributes to the inflammatory syndrome. Elevated ADMA levels in many rheumatological diseases suggest that ADMA might play an important role in the rheumatological diseases and cardiovascular complication. In this review, we discuss the role of ADMA in rheumatological disease's cardiovascular complications. Key words: Arginine/ME; Rheumatic diseases/CO/ME; Immune system diseases/CO/ME; Review

Possible role of asymmetric dimethylarginine (ADMA) in prediction of perinatal outcome in preeclampsia and fetal growth retardation related to preeclampsia

Objective: The objective of this study is to investigate maternal serum and neonatal umbilical cord asymmetric dimethylarginine (ADMA) levels in prediction of perinatal prognosis in pregnancies with preeclampsia (PE) and fetal intrauterine growth retardation (IUGR) accompanying PE (PE + IUGR).Methods: Maternal serum ADMA (msADMA) and neonatal umbilical cord ADMA (ucADMA) levels were studied from 34 patients with PE, 25 patients with PE + IUGR, and 30 healthy pregnant controls in this prospective case–control study. Umbilical artery Doppler indices of fetuses, birth weights, Apgar scores, umbilical artery pH measurements of neonates, and admissions to neonatal intensive care unit (NICU) were recorded.Results: Median msADMA was significantly higher in PE and PE + IUGR groups (p = 0.024 and p = 0.011, respectively), and ucADMA was significantly higher in PE and PE + IUGR groups than the control group (p = 0.029 and p = 0.018, respectively). Median msADMA and ucADMA levels were significantly higher in the PE + IUGR group than the PE group (p = 0.019 and 0.021, respectively). ucADMA levels did not correlate with fetal umbilical arterial blood flow neither in the PE nor in the PE + IUGR group (p = 0.518 and p = 0.892, respectively). None was related with neonatal umbilical artery pH or NICU admission rates.Conclusions: msADMA and ucADMA correlated with severity of PE. msADMA and ucADMA failed to predict perinatal outcome in patients with PE and PE + IUGR.

Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease.

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from L-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives.

Ammonia reduces intracellular ADMA level in cultured astrocytes and endothelial cells: possible involvement of increased y+LAT2-mediated efflux

Toxic effects of ammonia in the brain are partly related to impaired NO production which depending on the dose/time of ammonia exposure, may be either increased or decrease. Asymmetric dimethylarginine (ADMA), is endogenous NOSs inhibitor and symmetric dimethylarginine (SDMA) is arginine (Arg) transport inhibitor (Teerlink et al., 2009). Previously we reported an increase of ADMA and SDMA concentration in brain of rats with acute liver failure (Milewski et al., 2014), but distribution of the ADMA/SDMA surplus between the particular intra and extracellular compartments has not been studied. Here, we measured the intracellular concentration of ADMA, SDMA and ADMA/SDMA/NO precursor Arg, in cultured cortical astrocytes and rat brain endothelium cells (RBE-4) treated or not with ammonia. In RBE-4 cells not treated with ammonia the ADMA concentration was twice higher and the Arg/ADMA ratio was much lower than in astrocytes, confirming the well documented role of ADMA in endothelial NOS inhibition (Pope et al., 2009). Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell type. Since ammonia-dependent Arg transport in astrocytes is specifically mediated by the heteromeric Arg/Gln transporter y+LAT2 (Zielinska et al., 2012), we speculated that this may also hold for both Arg derivatives. Indeed, silencing of the y+LAT2 gene diminished the reduction of intracellular ADMA concentration caused by ammonia treatment in astrocytes. Moreover, the y+LAT2-dependent component of ammonia-evoked Arg uptake was reduced in the presence of ADMA in the medium. The results suggest that increased ADMA (and possibly SDMA) efflux mediated by upregulated y+LAT2 may be one of the ways in which ammonia interferes with intra-astrocytic ADMA content and, subsequently, NO synthesis. Studies are underway to establish if the same sequence of changes holds for ammonia-treated cerebral endothelial cells.

New Insights into Possible Role of NOS-NO-ADMA Pathway Dysfunction in the Development of Cognitive Decline and Dementia: Exploring the Vascular Features of Alzheimer’s Disease

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer’s disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO). Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health. NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. In the process of aging, the mechanisms by which NOS enzymes promote vascular dysfunction are specific for each NOS isoform. Normal activity of eNOS is required for the balanced production/bioavailability of NO, which is the main prerequisite for optimal vascular function. Conversely, excessive amount of NO produced by iNOS contributes to vascular dysfunction. Furthermore, although the possible role of nNOS-derived NO in aging-associated vascular dysfunction is far from being fully elucidated, experimental findings indicate that impaired perivascular NO release from nNOS increases vasoconstriction in aged arterioles. Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA). It has been recently proposed that ADMA may be a possible link between vascular disease and dementia. Based on this assumption ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. These observations were made based on good evidence from literature that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. However, possible role of ADMA in pathophysiology of cognitive decline and AD is still not fully understood. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. According to newly introduced hypothesis disturbed NOS-NO-ADMA pathway is one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell cultures and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases. Future research should also explain whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia. Moreover, clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.

Dimethylarginines as risk markers of atherosclerosis and chronic kidney disease in children with nephrotic syndrome.

Nephrotic syndrome in children is commonly associated with dyslipidemia, which is considered a risk factor for endothelial dysfunction and atherosclerosis. Recently new markers of endothelial dysfunction, such as asymmetric dimethylarginine (ADMA), have gained importance. Another L-arginine derivative--symmetric dimethylarginine (SDMA)--may reflect the glomerular filtration rate (GFR). The main aim of this study was to assess ADMA as a marker of atherosclerosis. Secondly, SDMA was examined for GFR assessment. The study involved 32 children with nephrotic syndrome. Several parameters were examined in the remission and relapse phases of nephrotic syndrome, including ADMA, SDMA, cholesterol, triglycerides and GFR. In the relapse phase there was a negative correlation between ADMA and lipids (cholesterol and triglycerides). In both phases SDMA was negatively correlated with GFR. The role of ADMA as a marker for endothelial dysfunction is not significant. SDMA may be utilized to monitor GFR in children with nephrotic syndrome.

Working Memory and Aphasia

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer’s disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO). Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health. NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. In the process of aging, the mechanisms by which NOS enzymes promote vascular dysfunction are specific for each NOS isoform. Normal activity of eNOS is required for the balanced production/bioavailability of NO, which is the main prerequisite for optimal vascular function. Conversely, excessive amount of NO produced by iNOS contributes to vascular dysfunction. Furthermore, although the possible role of nNOS-derived NO in aging-associated vascular dysfunction is far from being fully elucidated, experimental findings indicate that impaired perivascular NO release from nNOS increases vasoconstriction in aged arterioles. Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA). It has been recently proposed that ADMA may be a possible link between vascular disease and dementia. Based on this assumption ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. These observations were made based on good evidence from literature that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. However, possible role of ADMA in pathophysiology of cognitive decline and AD is still not fully understood. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. According to newly introduced hypothesis disturbed NOS-NO-ADMA pathway is one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell cultures and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases. Future research should also explain whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia. Moreover, clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.

Asymmetric dimethylarginine (ADMA) and treatment response relationship in male patients with first-episode schizophrenia: A controlled study

Nitric oxide (NO) is thought to be involved in the pathogenesis of schizophrenia as well as many neuropsychiatric disease. Asymmetric dimethylarginine (ADMA) reduces the level of NO by inhibiting nitric oxide synthase (NOS) enzyme. In this study it is aimed to be investigated ADMA in patients with first-episode schizophrenia. In this study, according to DSM-IV diagnostic criteria for schizophrenia-like psychotic disorder, 49 male first-episode schizophrenia patients—whose mean age was 23.4±3.5 year—and age and education matched 30 healthy male subjects were included for comparison. ADMA levels of the patients were measured before and after 2 months of therapy. In order to rule out the conditions that may affect the levels of ADMA, people whose physical examination and laboratory findings were within normal range were included in the study. In this study plasma ADMA levels of first-episode schizophrenia patients and control group were 3.6±1.5µmol/L and 1.02±1.02 respectively. After 2 months of antipsychotic treatment plasma ADMA levels of the schizophrenia patients decreased compared to baseline. There was no relationship between the ADMA levels and the clinical severity of the disease. It is considered to be the role of ADMA in the etiopathogenesis of schizophrenia.

Role of Asymmetric Dimethylarginine in Cardiorenal Syndrome

Cardiorenal syndrome (CRS) is a condition in which there is a complex interrelationship between cardiovascular disease (CVD) and chronic kidney disease (CKD). Impairment of one organ could accelerate pathological processes in the other, which in turn accelerates the progression of failure of both. Although clinical studies hint at a specific bidirectional interaction between cardiovascular system and kidney, insight into the pathogenesis of CRS remains unknown. One possible factor that could explain this link is endothelial dysfunction (ED). ED is not only involved in initiation and progression of atherosclerosis, but also contributes to progression of renal injury. Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase inhibitor found in the plasma and cells. Plasma ADMA levels are increased in CKD patients and known to be an independent biomarker and predictor for future cardiovascular events as well as the progression of CKD. These findings indicate that accumulated ADMA-mediated ED may play important roles in CRS in CKD patients. In this review, we discuss the roles of ADMA in the development of ED, especially focusing on its roles in CRS.

Dimethylarginines: Endogenous Inhibitors of Nitric Oxide Synthesis in Children With Falciparum Malaria

Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown. We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured. ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde-pendent-ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria. In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.

Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury

Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2′-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury–induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.

Role of Asymmetric Dimethylarginine in The Etiopathogenesis of Psychiatric Disorders: Review

Asimetrik dimetilarjinin, arjinin aminoasitinin translasyon sonrasinda modifiye olmus bir formudur. Asimetrik dimetilarjinini onemli kilan nitrik oksit sentaz enzimini yarismali olarak inhibe etmesidir. Gunumuze kadar yapilan arastirma ve gozlemler asimetrik dimetilarjinin birikiminin nitrik oksit sisteminde sinyal iletiminin duzenlenmesinde onemli bir role sahip olabildigini ve bu birikimin beyinde nitrik oksit uretiminin duzenlenmesinde yeni bir mekanizma oldugunu gostermektedir. Calismalar cesitli psikiyatrik bozukluklarda asimetrik dimetilarjinin duzeylerinin yukseldigini, bu yuksekligin nitrik oksit sentaz enziminde inhibisyon yaparak nitrik oksit uretimini azalttigini ve bu hastaliklarin fizyopatolojisinde yeri oldugunu ileri surmektedir. Bu derlemede gunumuze kadar psikiyatri hastalarinda yapilmis asimetrik dimetilarjinin ve nitrik oksit ile ilgili calisma sonuclari tartisilarak bu molekullerin cesitli psikiyatrik bozukluklarin etiyopatogenezindeki yeri ele alinmistir.

The Role of Asymmetric Dimethylarginine and Lipoprotein Associated Phospholipase A2 in Children and Adolescents with Dyslipidemia

Background: The pathophysiologic mechanisms which lead to cardiovascular (CV) events begin early in childhood. Atherosclerosis is recognized as a process of chronic and dynamic vascular inflammation induced primarily by endothelial dysfunction. Asymmetric dimethylarginine (ADMA) and lipoprotein associated phospholipase A2 (Lp-PLA2) are considered markers of early atherosclerosis and predictors of late complications in adults. Objectives: To establish the relationship between ADMA, Lp-PLA2 and traditional biochemically determined markers in children and adolescents with dyslipidemia. Material and Methods: The study population consisted of 102 children, 57 males/45 females, with a median age of 9.9 years. Seventy-one out of 102 had dyslipidemia (LDL-C levels ≥ 130 mg/dl). Lipid levels were estimated after an overnight fasting. LDL-C concentration was directly measured. ADMA and Lp-PLA2 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using STATA for Windows v8.5. Results: ADMA was significantly positively correlated with all TC, LDL-C and non-HDL-C. Even small changes of the ADMA concentration were found to be followed by corresponding alterations in lipid levels. A positive correlation of borderline significance between Lp-PLA2 and LDL-C or non- HDL-C was observed. In addition, ADMA and Lp-PLA2 were significantly correlated. A strong correlation between Lp-PLA2 and dyslipidemia or lipid levels could not be established, probably due to the size and heterogeneity of our sample. Conclusions: A relationship of ADMA and Lp-PLA2 levels with biochemical markers associated with long-term risk of atherosclerosis in children and adolescents is supported. The assessment of these two biomarkers combined may improve CV risk prediction and future management strategies in the pediatric population.

Asymmetric dimethylarginine and critical illness

Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient.

The cardiovascular risk marker asymmetric dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression

As lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric dimethylarginine concentrations were elevated in treatment naïve, HIV-infected subjects and to correlate these with markers of immune activation and disease progression. Serum samples were collected from HIV-positive and -negative subjects attending a primary health care clinic over a 12-month period. Asymmetric dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes. Sixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The mean asymmetric dimethylarginine concentration in the infected group measured 0.67 µmol/L (95% CI 0.62-0.72 µmol/L) which was significantly higher than in the control group of 0.48 µmol/L (95% CI 0.40-0.56 µmol/L). Asymmetric dimethylarginine correlated inversely with CD4 counts and positively with IgG, adenosine deaminase and CD8/38 T lymphocytes. No significant correlation was found with hsCRP, IL-6, or viral load. We demonstrated that asymmetric dimethylarginine is elevated in HIV infection, in patients with relatively well-preserved CD4 counts not yet on anti-retroviral treatment. We showed significant correlations of asymmetric dimethylarginine with CD8/38 T lymphocytes, IgG and adenosine deaminase, suggesting that T-cell activation and the adaptive immune response underlie asymmetric dimethylarginine elevation in this population.

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.

Role of asymmetrical dimethylarginine in the progression of renal disease

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Serum asymmetric dimethylarginine levels are independently associated with procollagen III N-terminal peptide in nonalcoholic fatty liver disease patients

Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes.

Asymmetric Dimethylarginine Plasma Levels and Endothelial Function in Newly Diagnosed Type 2 Diabetic Patients

It is now well established that major risk factors for cardiovascular diseases (CVD) impact upon endothelial function by decreasing nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA), an endogenous analog of l-arginine, is able to inhibit the activity of endothelial-NO synthase, promoting endothelial dysfunction. Type 2 diabetes (T2D) is characterized by a reduced endothelium-dependent vasodilation and increased ADMA levels and ADMA is strongly associated with micro- and macrovascular diabetic complications. However, there are not a lot of data about the role of ADMA on endothelial function in newly diagnosed T2D patients without cardiovascular (CV) complications. For this aim, we have enrolled forty-five newly diagnosed T2D patients, evaluated by a oral glucose tolerance test, and thirty normal subjects. Endothelium-dependent and -independent vasodilatation was investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh) and sodium nitroprusside. ADMA was measured by high-performance liquid chromatography and insulin resistance (IR) by HOMA. Newly diagnosed T2D patients showed higher ADMA and l-arginine mean values in comparison with normal subjects and a significantly reduced ACh-stimulated forearm blood flow (FBF). In T2D patients FBF was significantly and inversely correlated with ADMA (r = −0.524, p < 0.0001) and in a multivariate regression analysis, ADMA resulted the stronger predictor of FBF, explaining the 27.5% of variability (p < 0.0001). In conclusion, ADMA was strongly related to endothelial dysfunction also in patients with newly diagnosed T2D, without clinically manifest vascular complications. This field is of great interest for understanding the mechanisms underlying the pathogenesis of diabetic disease and its CV complications.

Atherosclerosis in Rheumatoid Arthritis

There is a growing body of evidence supporting an increased risk of cardiovascular (CV) mortality in patients with rheumatoid arthritis (RA). This is the result of complex mechanisms leading to accelerated atherosclerosis [1]. In this regard, besides classic CV risk factors [2], chronic inflammation [3] and a genetic component [3, 4] have been proposed to influence the development of atherosclerosis in RA. This special issue encompasses different aspects of the CV disease associated to RA. With respect to this, the link between atherosclerosis and RA was discussed. Surrogate markers of atherosclerosis have been found to be useful in predicting the presence of atherosclerosis disease in subclinical stages in adults with RA [5, 6]. Data shown in this special issue also confirmed that children with juvenile idiopathic arthritis may have higher carotid intima-media wall thickness index values than controls. These observations emphasize the need for increased awareness of the risk of atherosclerosis in children with juvenile idiopathic arthritis. An exhaustive literature review on the genetic influence in the development of CV disease in patients with RA was also included. With respect to this, it is important to keep in mind that besides gene polymorphisms located within the MHC region [3, 4], variations of genes located outside this region, such as CCR5, MTHF [7, 8], are of potential relevance in the increased risk of CV disease associated to RA. Adipokines are molecules not only implicated in the development of metabolic syndrome but also in inflammatory mechanisms that may play a role in the pathogenesis of different autoimmune diseases [9, 10]. A timely review on the implication of adipokines in the development of the atherosclerotic disease not only focusing on RA but also discussing the link between these molecules and the presence of atherosclerosis in other chronic inflammatory rheumatic diseases was included in the special issue. The mechanisms associated with endothelial dysfunction, an early step in the atherogenesis process, in patients with RA are far from being completely understood. In this special issue an assessment of the potential role of asymmetric dimethylarginine and apelin as biomarkers to detect early data of endothelial dysfunction in patients with RA was included. Anti-TNF-α drugs constitute the mainstay of therapy in RA patients with severe disease that is refractory to conventional disease modifying antirheumatic drugs. One of the articles included in the special issue confirmed the previously reported short-term beneficial effect of the fully human-anti-TNF-α monoclonal antibody adalimumab on endothelial function [11]. In addition, new data showing persistent improvement of endothelial function in adalimumab-treated RA patients without progression of the carotid intima-media thickness are reported. This is of potential relevance as the use of anti-TNF-α therapy has been associated with a decrease of mortality in RA patients, mainly due to a reduction in the incidence of CV events [12]. In line with the above, Popa et al. had previously assessed the effects of the anti-TNF-α therapy on the HDL antiatherogenic function. They observed that infliximab, a chimeric anti-TNF-α monoclonal IgG1 antibody was able to improve HDL antioxidative capacity. This effect was sustained 6 months after anti-TNF-α therapy had been initiated [13]. In this special issue the same group conducted an extensive review on the effect that different biologic therapies exert on the atherogenic index and HDL cholesterol in patients with RA. Taken together, these studies confirm the presence of complex mechanisms that influence the development of atherosclerosis in RA. Nevertheless, further studies are needed to shed light on the problem of augmented risk of CV disease in patients with RA. Miguel A. Gonzalez-Gay Zoltan Szekanecz Calin D. Popa Patrick Dessein