dimethylarginine and Inflammation

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Topics: Aorta; Arginine; Autonomic Nervous System Diseases; Bone Diseases, Metabolic; Cardio-Renal Syndrome; Cardiovascular Diseases; Chronic Disease; Endothelium, Vascular; Glycation End Products, Advanced; Humans; Inflammation; Myocardial Infarction; Oxidative Stress; Phosphorus; Renal Insufficiency, Chronic; Toxins, Biological; Tunica Intima; Uric Acid; Vascular Stiffness; Vasculitis

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Topics: Arginine; Creatinine; gamma-Aminobutyric Acid; Glutamic Acid; Glutamine; Homoarginine; Humans; Hydroxyproline; Immunologic Factors; Inflammation; Nutritional Requirements; Nutritional Status; Osteoarthritis; Proline; Tryptophan

Although the high risk for cardiovascular events in patients with end-stage renal disease (ESRD) is well known, recent data provide compelling evidence that even mild to moderate kidney disease is an important and independent risk factor for cardiac events. This increased risk does not seem to be explained by traditional risk factors as defined by the Framingham cohort. The examination of nontraditional risk factors has resulted in the identification of, among others, oxidant stress, hyperhomocystinemia, carbamylation, nitric oxide synthase inhibitors, and abnormal lipoproteins as potential pathways to explain the accelerated atherosclerosis in patients with kidney disease. Well-designed clinical trials should lead to the clarification of the relative importance of these factors in the pathogenesis of atherosclerotic disease.

Topics: Arginine; Cardiovascular Diseases; Humans; Hyperhomocysteinemia; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Lipoproteins; Lipoproteins, LDL; Nitric Oxide Synthase; Oxidative Stress; Proteinuria; Renal Dialysis; Risk Factors

Elevation of plasma homocysteine level is a risk factor for cardiovascular disease, stroke, and venous thromboembolism. It is still uncertain, however, whether hyperhomocysteinemia is a causative factor or a marker of vascular disease. The strongest evidence that homocysteine plays a causal role in atherothrombosis has been provided by studies using animal models. In the past decade, considerable progress in defining the vascular effects of hyperhomocysteinemia was achieved through the use of genetic and dietary approaches to induce hyperhomocysteinemia in experimental animals. A key vascular phenotype observed in hyperhomocysteinemic animals is endothelial dysfunction, manifested by decreased bioavailability of endothelium-derived nitric oxide. Impairment of endothelial function may be mediated by either accelerated oxidative inactivation of nitric oxide or inhibition of nitric oxide production caused by the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Hyperhomocysteinemia also increases susceptibility to arterial thrombosis and accelerates the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Mechanisms of atherothrombosis may include homocysteine-induced thiolation or acylation of plasma or endothelial proteins and endoplasmic reticulum stress, which activates signal transduction pathways leading to inflammation and apoptosis.

Topics: Animals; Apolipoproteins E; Apoptosis; Arginine; Atherosclerosis; Coronary Thrombosis; Cysteine; Disease Models, Animal; Endothelium, Vascular; Homocysteine; Humans; Hyperhomocysteinemia; Inflammation; Methionine; Mice; Models, Biological; Nitric Oxide; Oxidative Stress; Oxygen; Phenotype; Signal Transduction

Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. N9 microglial cells are used to gain mechanistic insights. Our POAG cohort showed elevated ATP in aqueous humor and cytokines in plasma. Metabolomic analysis showed changes in 21 metabolites including Dimethylarginine (DMAG) and activation of tryptophan metabolism in POAG. Analysis of GEO data sets and previously published proteomic data sets bins genes into signaling and metabolic pathways. Pathways from reanalyzed metabolomic data from literature significantly overlapped with those from our POAG data. DMAG modulated purinergic signaling, ATP secretion and cytokine expression were inhibited by N-Ethylmaleimide, NO donors, BAPTA and purinergic receptor inhibitors. ATP induced elevated intracellular calcium level and cytokines expression were inhibited by BAPTA. Metabolomics of cell culture supernatant from ATP treated sets showed metabolic deregulation and activation of tryptophan metabolism. DMAG and ATP induced IDO1/2 and TDO2 were inhibited by N-Ethylmaleimide, sodium nitroprusside and BAPTA. Our data obtained from clinical samples and cell culture studies reveal a strong association of elevated DMAG, ATP, cytokines and activation of tryptophan metabolism with POAG. DMAG mediated ATP signaling, inflammation and metabolic remodeling in microglia might have implications in management of POAG.

Topics: Adenosine Triphosphate; Aqueous Humor; Arginine; Cytokines; Female; Glaucoma, Open-Angle; Humans; Inflammation; Male; Microglia; Tryptophan

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.

Topics: Arginine; Atherosclerosis; Coronary Artery Disease; Disease Progression; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Inflammation; Male; Pilot Projects; Prognosis; Vasodilation

Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure.. We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA.. In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading.. Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction.. Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.

Topics: Adult; alpha-Tocopherol; Arginine; Ascorbic Acid; Cholesterol, LDL; Chronic Disease; Cytokines; Double-Blind Method; Endothelium, Vascular; Female; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Inflammation; Interleukin-6; Male; Methionine; Oxidative Stress; Time Factors; Vascular Resistance; von Willebrand Factor

The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated.. In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography.. FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet.. This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.

Topics: Adolescent; Adult; Arginine; Biomarkers; Child; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Cross-Over Studies; Docosahexaenoic Acids; Double-Blind Method; Endothelium, Vascular; Humans; Hyperlipidemia, Familial Combined; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Inflammation; Oxidative Stress; Phenotype; Triglycerides

Symmetric (SDMA) and asymmetric (ADMA) dimethylarginines have emerged as novel biomarkers of cardiovascular disease (CVD) in several disease settings associated with atherosclerosis. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by high CVD mortality and morbidity. ADMA and SDMA levels are abnormal in RA patients, but their correlation with assessments of endothelial function and structure remains unknown. We aimed to investigate whether SDMA and ADMA are associated with carotid intima media thickness (cIMT) and arterial stiffness as well as non-invasive assessments of in vivo micro- and macrovascular endothelial function in RA patients with high systemic inflammatory load.. ADMA and SDMA levels were measured using immunoassays in 197 RA individuals. Twenty-six of these [23 (86.4%) females, median age 70, quartiles (60, 73)] were identified as having high inflammatory markers [erythrocyte sedimentation rate (ESR) >25 mm/hr and C-reactive protein (CRP) > 5 mg/L], and were compared to the remainder of the cohort. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function [laser Doppler imaging with iontophoresis of acetylcholine (Ach) and sodium-nitroprusside (SNP) respectively], macrovascular endothelium-dependent and endothelium-independent function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilation respectively), and vascular morphology [pulse wave analysis, and carotid intima media thickness (cIMT)].. Significant interactions with inflammation were detected in the associations between ACh and both SDMA (p = 0.014) and ADMA:SDMA ratio (p = 0.027), as well as between SNP and SDMA (p = 0.042) and between arterial stiffness and ADMA:SDMA (p = 0.036), with the associations being stronger in the patients with high inflammatory markers in each case.. Besides their emerging role as markers of endothelial dysfunction SDMA and ADMA may promote endothelial injury in RA as mediators of the adverse effects of systemic inflammation on micro- and macrovasculature respectively in patients with active disease.

Topics: Aged; Arginine; Arthritis, Rheumatoid; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cohort Studies; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoassay; Inflammation; Laser-Doppler Flowmetry; Male; Middle Aged; Pulse Wave Analysis; Receptor Cross-Talk; Vascular Stiffness

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.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Arginine; Dexamethasone; Diet, High-Fat; Female; Inflammation; Insulin-Like Growth Factor I; Liver; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; RNA, Messenger; Sensation Disorders; Space Perception; Tumor Necrosis Factor-alpha

Leptospirosis is one of the most relevant zoonosis worldwide and a potentially life-threatening infectious disease. While it is frequent in tropic regions, it is uncommon in European industrialized countries. Angiopoietin-2 (Angpt-2) and asymmetric and symmetric dimethylarginine (ADMA and SDMA) are markers of endothelial activation and systemic inflammation. These parameters have been studied recently in the context of sepsis and MODS showing potential to determine disease severity and outcome specific parameters like acute kidney injury (AKI) and survival. These biomarkers were measured in 13 patients with leptospirosis. High levels of Angpt-2 were statistically significant associated with a complicated clinical course with occurrence of AKI, Sepsis and intensive care unit treatment. ADMA was significantly associated with occurrence of AKI and ICU treatment whereas SDMA was associated with AKI. Therefore these endothelial markers may serve as additional tools for risk stratification in these patients.

Topics: Acute Kidney Injury; Adult; Angiopoietin-2; Arginine; Biomarkers; Female; Humans; Inflammation; Intensive Care Units; Leptospirosis; Male; Middle Aged; Sepsis; Severity of Illness Index

Left atrial (LA) remodeling associated with atrial fibrillation (AF) is known to be related to inflammation and collagen turnover. We investigated the changes in the biomarkers of inflammation and collagen turnover in relation to LA reverse remodeling during the 1st year after AF ablation.. Biomarkers of inflammation [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)] and collagen turnover [matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), transforming growth factor beta 1 (TGF-β1)], as well as asymmetric dimethylarginine (ADMA) and adiponectin levels were measured, and echocardiographic measurements were obtained before and 3, 6, and 12 months after ablation in 60 AF patients (49 males; age, 57.6 ± 10.9 years).. During a 12.1 (11.5-12.9)-month follow-up period, AF recurred in 29 patients (48 %). Neither the LA volume (LAV) nor the left ventricular ejection fraction (LVEF) changed significantly during the 1st year in this group, but the LAV decreased significantly, and the LVEF increased significantly in the nonrecurrence group. The hs-CRP and IL-6 decreased after ablation but returned near to baseline levels in both groups by 12 months. The MMP-2 remained increased during the 1st year in both groups, whereas the TIMP-2 increased markedly in the nonrecurrence group but did not change substantially in the recurrence group. The TGF-β1 increased in both groups, but the change was less pronounced in the recurrence group. The ADMA and adiponectin levels did not change substantially in either group.. Despite reverse remodeling, the inflammation and collagen turnover biomarker levels are quite progressive during the 1st year after ablation and may explain the late AF recurrence.

Topics: Adiponectin; Arginine; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Catheter Ablation; Diagnostic Imaging; Echocardiography; Electrocardiography; Extracellular Matrix; Female; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 2; Middle Aged; Predictive Value of Tests; Recurrence; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Treatment Outcome

Alzheimer's disease (AD) is the most common type of dementia accounting for 60-80% of the reported cases. The aim of this study was to evaluate levels of certain parameters of oxidative stress and markers of endothelial dysfunction in the blood of 21 AD patients under standard treatment compared with 10 controls, in an attempt to elucidate the contribution of AD to the total oxidative stress status of the patients. Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil-Memantine, respectively Donepezil group. Although the study is based on a limited population, the results could constitute the basis for further studies regarding the effect of medication and diet on AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Arginine; Biomarkers; Case-Control Studies; Endothelium, Vascular; Female; Glutathione; Homocysteine; Humans; Inflammation; Interleukin-6; Male; Oxidative Stress; Protein Carbonylation; Tumor Necrosis Factor-alpha

There is growing evidence that increased levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to endothelial dysfunction. Studies in animal models as well as in humans have suggested that the increase in ADMA occurs at a time when vascular disease has not yet become clinically evident. ADMA competitively inhibits NO elaboration by displacing L-arginine from NO synthase. In a concentration-dependent manner, it thereby interferes not only with endothelium-dependent, NO-mediated vasodilation, but also with other biological functions exerted by NO. The upshot may be a pro-atherogenic state. Recently, several studies have investigated the effect of various therapeutical interventions on ADMA plasma concentrations.

Topics: Animals; Arginine; Cardiovascular Diseases; Humans; Inflammation; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Reactive Oxygen Species; Risk Factors

 Endothelial dysfunction and accumulation of asymmetric dimethylarginine (ADMA) have been identified as independent predictors of future cardiovascular events in patients with coronary artery disease..  The aim of the study was to investigate the factors that determine increased accumulation of ADMA, an endogenous inhibitor of nitric oxide synthesis, in patients with rheumatoid arthritis (RA)..  We studied 46 consecutive patients with RA (39 women, 7 men; mean age, 57 years [range, 23-75 years]) with active disease (mean Disease Activity Score 28 [DAS28], 5.2), without clinically overt cardiovascular disease and 50 controls matched for age, sex, hypertension, blood cholesterol, and glucose. We assessed the plasma levels of ADMA, symmetric dimethylarginine (SDMA), L‑arginine, and the marker of oxidative stress, 8‑iso‑prostaglandin F2α (8‑iso‑PGF2α). .  ADMA and SDMA levels were significantly higher in the RA group than in controls (0.58 ±0.081 vs. 0.46 ±0.045 μmol/l, P <0.0001; 0.45 ±0.07 vs. 0.36 ±0.046 μmol/l, P <0.0001; respectively). ADMA levels in the RA group correlated positively with fibrinogen (r = 0.70, P <0.00001), C‑reactive protein (CRP; r = 0.88, P <0.00001), DAS28 (r = 0.44, P = 0.002) and Health Assessment Questionnaire scores (r = 0.39, P = 0.008), but not with age, renal function, or the medications used. 8‑iso‑PGF2α correlated positively with ADMA (r = 0.82), SDMA (r = 0.72), CRP (r = 0.76), fibrinogen (r = 0.57) (all, P <0.0001) and DAS28 (r = 0.44, P = 0.003). Regression analysis models showed that CRP was the only independent predictor of 8‑iso‑PGF2α and ADMA levels in RA..  Our study is the first to show positive associations between plasma ADMA levels and the production of 8‑isoprostanes and CRP in RA.

Topics: Adult; Aged; Arginine; Arthritis, Rheumatoid; Biomarkers; Female; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Young Adult

Metabolic syndrome (MS) is a constellation of metabolic derangements associated with vascular endothelial dysfunction and oxidative stress and is widely regarded as an inflammatory condition, accompanied by an increased risk for cardiovascular disease. The present study tried to investigate the implications of telomerase activity with inflammation and impaired endothelial function in patients with metabolic syndrome. Telomerase activity in circulating peripheral blood mononuclear cells (PBMC), TNF-α, IL-6 and ADMA were monitored in 39 patients with MS and 20 age and sex-matched healthy volunteers. Telomerase activity in PBMC, TNF-α, IL-6 and ADMA were all significantly elevated in patients with MS compared to healthy volunteers. PBMC telomerase was negatively correlated with HDL and positively correlated with ADMA, while no association between TNF-α and IL-6 was observed. IL-6 was increasing with increasing systolic pressure both in the patients with MS and in the healthy volunteers, while smoking and diabetes were positively correlated with IL-6 only in the patients' group. In conclusion, in patients with MS characterised by a strong dyslipidemic profile and low diabetes prevalence, significant telomerase activity was detected in circulating PBMC, along with elevated markers of inflammation and endothelial dysfunction. These findings suggest a prolonged activity of inflammatory cells in the studied state of this metabolic disorder that could represent a contributory pathway in the pathogenesis of atherosclerosis.

Topics: Adult; Aged; Arginine; Biomarkers; Blood Pressure; Case-Control Studies; Endothelium, Vascular; Female; Greece; Humans; Inflammation; Interleukin-6; Leukocytes, Mononuclear; Lipoproteins, HDL; Male; Metabolic Syndrome; Middle Aged; Oxidative Stress; Telomerase; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the pro-oxidant and proinflammatory biomarkers and their relationship with dimethylarginines (DMAs) in patients at various stages of chronic kidney disease (CKD). We studied 114 CKD patients, 36 were hemodialyzed, 41 peritoneal dialyzed and 37 nondialyzed (early stage) CKD patients. The control group consisted of 31 healthy subjects. Plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-arginine, nitric oxide (NO) and proinflammatory cytokines (TNF-alpha and IL-6) were determined, and their relationships with the degree of disease were evaluated. Both DMAs were at high levels in all CKD patients, whereas arginine concentrations were low in patients undergoing dialysis. Elevated TNF-alpha and IL-6 in CKD patients were indicative of ongoing chronic inflammatory state. A significant positive correlation between SDMA and creatinine suggests that plasma SDMA level may be an index for renal function.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arginine; Biomarkers; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Nitric Oxide; Renal Dialysis; Renal Insufficiency; Tumor Necrosis Factor-alpha; Young Adult

Increasing evidence suggests that the postprandial state is a contributing factor to the development of atherosclerosis. To evaluate the effects of acute hyperglycemia on endothelial dysfunction and inflammation, plasma asymmetrical dimethyl-l-arginine (ADMA), intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, and C-reactive protein (CRP) levels and secretory phospholipase A(2) (sPLA(2)) activities were measured in subjects with normal (n = 35), impaired (IGT) (n = 25), and diabetic (DGT) (n = 20) glucose tolerance. At baseline, plasma ADMA, sICAM-1, and CRP concentrations and plasma sPLA(2) activities were higher in both the IGT and DGT groups than in the normal glucose tolerance group (for each comparison, each P < .001). Patients with DGT have higher plasma ADMA and sICAM-1 concentrations than patients with IGT (for each, P < .001).Two hours after glucose loading, plasma ADMA and CRP concentrations and sPLA(2) activities were significantly elevated in the 3 groups when compared with baseline levels (for each comparison, P < .001). Plasma vascular cell adhesion molecule 1 and sICAM-1 concentrations were found to be elevated from baseline levels after glucose loading in the IGT and DGT groups (for each comparison, P < .001). Correlation analysis at baseline suggested that there was a significant relationship between ADMA and inflammation and soluble adhesion markers in the studied groups. In conclusion, plasma concentrations of ADMA and of inflammation and adhesion molecules were elevated in the prediabetic state. A complex interrelation could exist between ADMA and inflammation, and mechanisms involved in endothelial dysfunction are multifactorial at the prediabetic and diabetic state.

Topics: Adult; Arginine; Blood Pressure; C-Reactive Protein; Diabetes Mellitus; Female; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Reference Values; Vascular Cell Adhesion Molecule-1

Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. The pathophysiology of multiorgan dysfunction in ALF remains unclear but increased systemic inflammatory response is believed to be an important determining factor. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, results from proteolysis and the liver is a major site for its metabolism. ADMA has been shown to independently predict outcome in multiorgan failure associated with severe liver dysfunction. In this study, we tested the hypothesis that proinflammatory cytokine driven responses are important in modulating ADMA levels in patients with acetaminophen-induced ALF. Blood samples were collected from 10 ALF patients (grade IV encephalopathy) from admission until the time of transplantation or death, and assayed for cytokines and ADMA. A total of 8 patients required treatment for raised intracranial pressure and all patients were managed with standard of care, including full mechanical ventilation and veno-venous hemofiltration. ADMA levels were markedly higher in ALF patients compared to age-matched controls (P < 0.001) and correlated with the levels of proinflammatory cytokines. In pretransplantation patients undergoing hepatic venous catheterization, we demonstrated no significant uptake of ADMA across the failing liver. However, following liver transplantation, ADMA levels reduced acutely. A timed study of ADMA levels during transplantation demonstrated a slight increase during the anhepatic phase but a marked and sustained reduction in ADMA following liver reperfusion. In conclusion, our data show a significant correlation between ADMA levels and proinflammatory cytokines, supporting a hypothesis that proinflammatory cytokines may regulate ADMA metabolism in ALF.

Topics: Adult; Arginine; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Liver; Liver Failure, Acute; Male; Middle Aged; Nitric Oxide Synthase; Predictive Value of Tests; Severity of Illness Index; Tumor Necrosis Factor-alpha