dimethylarginine and Atherosclerosis

Cardiovascular diseases are the most common diseases worldwide. They are responsible for one third of global deaths and they are the leading cause of disability, too. The usage of different levels of prevention in combination with effective risk assessment improved these statistical data. Risk assessment based on classic risk factors has recently been supported with several new markers, such as asymmetric dimethylarginine, which is an endogenous competitive inhibitor of nitric oxide synthase. Elevated levels of asymmetric dimethylarginine have been reported in obese, smoker, hypercholesterolemic, hypertensive and diabetic patients. According to previous studies, asymmetric dimethylarginine is a suitable indicator of endothelial dysfunction, which is held to be the preceding condition before atherosclerosis. Several researches found positive correlation between higher levels of asymmetric dimethylarginine and coronary artery disease onset, or progression of existing coronary disease. According to a study involving 3000 patients, asymmetric dimethylarginine is an independent risk factor of cardiovascular mortality in patients with coronary artery disease. This article summarizes the role of asymmetric dimethylarginine in prediction of cardiovascular diseases, and underlines its importance in cardiovascular prevention.

Topics: Arginine; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Humans; Nitric Oxide Synthase; Predictive Value of Tests; Risk Assessment; 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

To examine associations between asymmetric (ADMA), symmetric dimethylarginine (SDMA) and ADMA:SDMA ratio with assessments of endothelial function and coronary artery perfusion in RA patients.. ADMA and SDMA levels were measured in 197 RA individuals [144 (77.4%) females, median age: 66 years (quartiles: 59-73)]. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-dependent and endothelium-independent function and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Coronary perfusion was assessed by subendocardial viability ratio (SEVR).. SEVR correlated with SDMA (r = 0.172, p = 0.026) and ADMA:SDMA (r = -0.160, p = 0.041) in univariable analysis, but not in multivariable analysis accounting for confounding factors. Neither ADMA:SDMA ratio nor SDMA were significantly correlated with microvascular or macrovascular endothelial function, or with arterial stiffness and cIMT. Within subgroup of patients (n = 26) with high inflammatory markers, a post-hoc analysis showed that SDMA and the ADMA:SDMA ratio were significantly associated with endothelium-dependent microvascular function in univariable analysis, with Pearson's r correlation coefficients of -0.440 (p = 0.031) and 0.511 (p = 0.011), respectively. Similar finding were established between ADMA:SDMA ratio and arterial stiffness in univariable analysis, with Pearson's r of 0.493, (p = 0.024).. Dimethylarginines were not found to be significantly associated with several assessments of vascular function and morphology in patients with RA, however, post-hoc analysis indicates that there may be associations in patients with raised inflammatory markers. Our results suggest that dysregulated NO metabolism may not be the sole mechanism for the development of preclinical atherosclerosis in RA.

Topics: Aged; Arginine; Arthritis, Rheumatoid; Atherosclerosis; Carotid Artery Diseases; Carotid Intima-Media Thickness; Endothelium, Vascular; Female; Humans; Immunoenzyme Techniques; Microvessels; Middle Aged; Models, Biological; Prospective Studies; Pulse Wave Analysis; Ultrasonography

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

The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.

Topics: Anticholesteremic Agents; Arginine; Atherosclerosis; Atorvastatin; Cross-Sectional Studies; Dinoprost; Double-Blind Method; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Pravastatin; Pyrroles; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Asymmetric dimethylarginine (ADMA) is a recently identified potent cardiovascular risk factor. ADMA levels are increased in hyperhomocysteinaemia and the metabolism of ADMA is linked with that of homocysteine in several ways. Treatment with B vitamins effectively reduces homocysteine levels, but studies investigating the effect on ADMA levels are scarce and show conflicting results. In this study we evaluated the effect of treatment with B vitamins on ADMA levels in two high cardiovascular risk populations.. In study I, 110 siblings of patients with clinical atherosclerotic disease and postmethionine hyperhomocysteinaemia were treated with 5 mg of folic acid and 250 mg of pyridoxine or placebo, and were analysed after 1 year. In study II, 41 patients with type 2 diabetes and mild hyperhomocysteinaemia were analysed after 6 months treatment with 5 mg of folic acid or placebo.. A correlation between baseline homocysteine and ADMA levels was found, which was partly due to confounding by renal function. Homocysteine levels decreased by 43% in study I and by 28% in study II. In both studies, treatment with B vitamins had no effect at all on ADMA, arginine/ADMA ratio and SDMA levels. This result was confirmed in multiple linear regression analyses with adjustment for baseline values and gender.. Our studies indicate that B vitamins, despite causing a substantial reduction in plasma homocysteine levels, have no beneficial effect on ADMA levels.

Topics: Adolescent; Adult; Arginine; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Folic Acid; Humans; Hyperhomocysteinemia; Linear Models; Male; Middle Aged; Pyridoxine; Risk Factors; Time Factors; Treatment Failure; Vitamin B Complex

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality.. We evaluated up to 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium [ln (CAC+1)] and carotid intima-media thickness (IMT). In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values (βADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.11, 0.39]). Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values (βLTL -0.08, 95%CI -0.14, -0.02, and βIGF-1 -0.04, 95%CI -0.08, -0.01, respectively). During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality (hazard ratios [HR] per SD increase in biomarker, 0.85, 95% CI 0.74-0.99, and 0.90, 95% CI 0.82-0.98 for LTL and IGF-1, respectively). F2-Isoprostanes and ADMA values were positively associated with all-cause mortality (HR per SD increase in biomarker, 1.15, 95% CI, 1.10-1.22, and 1.10, 95% CI, 1.02-1.20, respectively).. In our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

Topics: Adult; Aged; Aged, 80 and over; Aging; Arginine; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Creatinine; Cross-Sectional Studies; Endothelial Cells; Female; Humans; Insulin-Like Growth Factor I; Isoprostanes; Male; Middle Aged; Oxidative Stress; Prospective Studies; Telomere Homeostasis; Telomere Shortening

Topics: Amidohydrolases; Animals; Arginine; Atherosclerosis; Endothelial Cells; Humans; Hyperuricemia; Mice; Nitric Oxide

Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.

Topics: Adult; Animals; Arginine; Arterial Pressure; Atherosclerosis; Child; Endothelium; Humans; Hypertension; Immunity, Innate; Inflammation Mediators; Kidney Diseases; Lipoproteins, HDL; Mice; Mice, Inbred C57BL; Nitric Oxide; Signal Transduction; Superoxides; Toll-Like Receptor 2; Wound Healing

The present study investigated the effects of 3'-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), the active principle compound of kimchi, on vascular damage in the experimental atherosclerotic animal. HDMPPA was administrated by an intraperitoneal injection of 10 mg/kg per d for 8 weeks to apoE knockout (KO) mice with an atherogenic diet containing 1 % cholesterol, and its effects were compared with vehicle-treated control mice. HDMPPA increased NO content in the aorta, accompanied by a decrease in reactive oxygen species (ROS) concentration. Furthermore, in the HDMPPA-treated group, aortic endothelial NO synthase (eNOS) expression was up-regulated compared with the control group. These results suggested that HDMPPA could maintain NO bioavailability through an increasing eNOS expression and preventing NO degradation by ROS. Furthermore, HDMPPA treatment in apoE KO mice inhibited eNOS uncoupling through an increase in vascular tetrahydrobiopterin content and a decrease in serum asymmetric dimethylarginine levels. Moreover, HDMPPA ameliorates inflammatory-related protein expression in the aorta of apoE KO mice. Therefore, the present study suggests that HDMPPA, the active compound of kimchi, a Korean functional food, may exert its vascular protective effect through the preservation of NO bioavailability and suppression of the inflammatory response.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Aortitis; Apolipoproteins E; Arginine; Atherosclerosis; Biopterins; Cell Adhesion Molecules; Diet, Atherogenic; Disease Models, Animal; Down-Regulation; Injections, Intraperitoneal; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Phenyl Ethers; Propionates; Random Allocation; Reactive Oxygen Species; Up-Regulation

An association between systemic autoimmune diseases and atherosclerosis has been described in many connective tissue diseases, and this association is known to lead to increased cardiovascular morbidity and mortality. Systemic sclerosis (SSc) is characterized by multisystem organ inflammation, endothelial wall damage, and vasculopathy. There are many markers of endothelial dysfunction and/or atherosclerotic risk, such as asymmetric dimethylarginine (ADMA), arterial stiffness parameters, carotid intima-media thickness (CIMT), and coronary flow reserve (CFR) assessed by transthoracic echocardiography. The aim of this pilot study was to use various endothelial and atherosclerosis markers to identify early cardiovascular involvement in a group of SSc patients.. The study involved 20 patients (2 men and 18 women with a mean ± SD age of 52.96 ± 12.51 years) with diffuse SSc who had no signs or symptoms of cardiovascular disease (CVD) and 20 age- and sex-matched controls. All subjects underwent a dipyridamole echocardiographic stress test that included a determination of CFR and an evaluation of CIMT, arterial stiffness, and plasma ADMA levels.. All of the arterial wall measurements of the patients with diffuse SSc were significantly different from those of the controls, and both right and left CIMT, pulse wave velocity, and stiffness index (β) were significantly elevated in the SSc patients compared to the healthy controls. Moreover, in patients with diffuse SSc, CFR was significantly lower (P = 0.0033) and plasma ADMA levels were higher (P < 0.0001) than in healthy controls.. SSc patients without any clinical evidence of CVD seem to have had subclinical atherosclerosis, which was suggested by early impairment of coronary microcirculation and macrovascular involvement.

Topics: Adult; Aged; Arginine; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Coronary Circulation; Cross-Sectional Studies; Echocardiography; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Pilot Projects; Scleroderma, Diffuse; Vascular Stiffness

Anti-apolipoprotein A-1 (anti-apoA-1) IgG is a potential marker of atherosclerotic plaque vulnerability and cardiovascular complications. In patients with periodontitis the presence of anti-apoA-1 IgGs in serum and their association with atherosclerosis is unknown.. One-hundred and thirty subjects with periodontal disease and 46 healthy subjects, matched for age and gender, participated in this study. Anti-apoA-1 IgG, high-sensitivity C-reactive protein (hsCRP) and matrix metalloproteinase (MMP) -2, -3, -8 and -9 were measured in serum samples. An ankle-brachial index (ABI) value below 1.11 served as a surrogate marker of atherosclerosis. Predictive accuracies of biomarkers for abnormal ABI were determined using receiver-operating characteristics curves and logistic regression analyses.. Compared with healthy controls, periodontitis patients showed lower median ABI values (1.10 vs. 1.15; p < 0.0001), a higher prevalence of anti-apoA-1 IgG positivity (23.8% vs. 6.5%; p = 0.009) and higher concentrations of hsCRP (1.62 mg/L vs. 0.85 mg/L; p = 0.02) and MMP-9 (435 μg/mL vs. 283 μg/mL; p < 0.0001). In patients younger than 50 years of age (n = 66), anti-apoA-1 IgG was found to be the best predictor for an abnormal ABI (area under the curve = 0.63; p = 0.03). Anti-apoA-1 IgG positivity increased the risk of having an abnormal ABI (odds ratio = 4.20; p = 0.04), independently of diabetes, smoking and body mass index.. Anti-apoA-1 IgG positivity and atherosclerosis, as reflected by abnormal ABI, were more prevalent in periodontitis patients than in age- and gender-matched controls. In younger periodontitis patients, anti-apoA-1 IgG was found to be the best predictor of atherosclerosis burden.

Topics: Adult; Ankle Brachial Index; Apolipoprotein A-I; Arginine; Atherosclerosis; Autoantibodies; Biomarkers; C-Reactive Protein; Case-Control Studies; Chi-Square Distribution; Chronic Periodontitis; Female; Humans; Immunoglobulin G; Logistic Models; Male; Matrix Metalloproteinases; Middle Aged; Predictive Value of Tests; ROC Curve; Statistics, Nonparametric

Atherosclerotic cardiovascular diseases are among the major causes of mortality in renal transplant (RT) patients. Oxidative stress plays an important role in the pathogenesis of atherosclerosis. In this study, we investigated the role of asymmetric dimethylarginine (ADMA) along with oxidized LDL (oxLDL) and antioxidized LDL (anti-oxLDL) on the extent and progression of atherosclerosis measured by carotid artery intima-media thickness (CA-IMT) in RT patients.. One hundred and eighty renal transplant patients were studied. Baseline and 25th month CA-IMT were determined by B-mode Doppler ultrasonography. ADMA, oxLDL and anti-oxLDL were measured by commercially available ELISA.. The mean age of the patients was 41 ± 9 years. The mean CA-IMT at baseline was 0.61 ± 0.15 mm. Age, cardiovascular disease and diabetes history, proteinuria and triglyceride levels were positively correlated, whereas HDL and albumin were negatively correlated with baseline CA-IMT. Ninety-two patients underwent a second CA-IMT measurement at a mean follow-up of 25th months. The mean second CA-IMT was 0.68 ± 0.18 mm. Serum ADMA levels, HCV positivity and albumin levels were predictors for CA-IMT progression in the multivariate analysis that included age, HCV positivity ADMA, albumin, glucose and proteinuria. OxLDL and anti-oxLDL were not associated with both CA-IMT presence and progression.. Serum ADMA levels predict progression of atherosclerosis in RT patients.

Topics: Adolescent; Adult; Aged; Antibodies, Viral; Arginine; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Disease Progression; Female; Hepacivirus; Humans; Kidney Transplantation; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Prospective Studies; Serum Albumin; Young Adult

Free asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide synthases (NOS). Suppression of nitric oxide (NO) synthesis increases the risk of atherosclerosis. Nevertheless, in the condition of oxidative stress, NOS blockade by ADMA may exert protective effects. Protein metabolism is altered in patients with phenylketonuria (PKU) on dietary treatment and as shown recently, oxidative stress is high in PKU. Since free ADMA concentrations are determined by both protein metabolism and oxidative stress we hypothesized, that free ADMA levels may be elevated in PKU patients.. Sixteen patientswith PKU on dietary treatment (mean age 10.1 ± 5.2 yrs), and 91 healthy children (mean age 11.6 ± 3.7 yrs) participated in a cross sectional study.. ADMA, total homocysteine (tHcy) and blood glucose were lower and the L-arginine/ADMA ratio was higher in PKU patients compared to controls. No significant correlation was present between phenylalanine (Phe) concentrations, protein intake, and lipid profile, history of cardiovascular disease or ADMA.. In contrast to our hypothesis, ADMAwas lower and the L-arginine/ADMA ratio was higher in PKU patients. Therefore, in PKU patients, the regulating function of ADMA on NO synthesis is altered and may thus contribute to oxidative stress.

Topics: Adolescent; Arginine; Atherosclerosis; Blood Glucose; Cardiovascular Diseases; Child; Cross-Sectional Studies; Female; Homocysteine; Humans; Lipid Metabolism; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Phenylalanine; Phenylketonurias

Nε-homocysteinyl-lysine (Nε-Hcy-Lys), a product of proteolysis of Nε-homocysteinylated proteins, has been discovered recently. We sought to investigate the presence of Nε-Hcy-Lys in patients on long-term hemodialysis (HD) and its association with markers involved in atherosclerotic vascular disease.. We studied 86 patients on long-term (median, 45 months) HD and 95 apparently healthy controls. Nε-Hcy-Lys and total homocysteine (tHcy) were assayed using high-performance liquid chromatography. Paraoxonase 1 (PON1), asymmetric dimethylarginine (ADMA), folate, 8-isoprostaglandin F2α(8-iso-PGF2α), plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), together with antibodies against Nε-homocysteinylated albumin and hemoglobin, were also measured.. Nε-Hcy-Lys was detected in 15 HD patients (17.4%). Those patients had 3.1-times lower PON1 (p<0.0001), 20% higher ADMA (p<0.0001), 30% higher PAI-1 (p<0.0001), 10% lower total cholesterol (p=0.001) and LDL-cholesterol (p<0.0001), together with 20% lower triglycerides (p<0.0001) compared with subjects without measurable Nε-Hcy-Lys. Nε-Hcy-Lys levels correlated with PON1 (r=-0.62, p<0.0001), ADMA (r=0.58, p<0.0001) and PAI-1 (r=0.59, p<0.0001). Folic acid supplementation, tHcy, folate, autoimmune response to Nε-Hcy-proteins, and oxidative stress were not associated with the presence of Nε-Hcy-Lys. PON1 is the only independent predictor of the presence of Nε-Hcy-Lys in HD patients. None of controls had measurable Nε-Hcy-Lys in serum.. The presence of Nε-Hcy-Lys in HD patients is relatively infrequent and associated with lipid profile, endothelial dysfunction and impaired fibrinolysis, regardless of tHcy and folate levels.

Topics: Aged; Antibodies; Arginine; Atherosclerosis; Biomarkers; Dipeptides; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Atherosclerosis is a chronic inflammatory disease, which selectively involves the arteries in the vascular system. Atherosclerosis develops because of reactions occurring in vessel wall beginning with response to endothelial injury. Endothelial dysfunction is characterized with impairment and loss of monolayer cells covering the inside of the vessels, which is endothelium. Endothelial dysfunction is the first stage in atherosclerosis. Coronary angiogenesis and collateral growth are chronic adaptations to myocardial ischemia to restore coronary blood flow and salvage myocardium in the ischemic region. Nitric oxide (NO) which represents the status of endothelial health plays a major role in collateral vessel development. Asymmetric dimethylarginine (ADMA) which is endogenous inhibitor of NO synthesis may impair the effective coronary collateral vessel development. Increased plasma ADMA levels are related with poor coronary collateral development. ADMA may be responsible for the difference in coronary collateral vessel development among similar patients with coronary artery disease. Nitric oxide inhibitors have a determinative relation with endothelial cell functions which may be integral prerequisite in all steps of collateral development. The aim of this review is to evaluate the interrelations between ADMA and collateral growth.

Topics: Arginine; Atherosclerosis; Cardiovascular Diseases; Collateral Circulation; Coronary Artery Disease; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Risk Factors

Previous investigations have indicated that reduced erythrocyte deformability may be an important factor contributing to the development of atherosclerosis, and endogenous asymmetric dimethylarginine (ADMA) might be an important contributor to reduction of erythrocyte deformability in atherosclerosis. In this study, the effect of 3,4,5,6-tetrahydroxyxanthone (1), a kind of polyphenolic compound, on erythrocyte deformability in apolipoprotein E-deficient (apoE-/-) mice was evaluated. After treatment with compound 1 (10 or 20 mg/kg per day) for 4 weeks, erythrocyte deformability, antioxidant enzymes activity, erythrocyte dimethylarginine dimethylaminohydrolase (DDAH) activity, the plasma level of ADMA and malondialdehyde (MDA) level were determined. Treatment with compound 1 (10 or 20 mg/kg) increased erythrocyte deformability, antioxidant enzymes activity concomitantly, a decrease in the plasma levels of MDA and ADMA, and an increase in erythrocyte DDAH activity. The present result suggests that the beneficial effect of 1 on the erythrocyte deformability, besides inhibiting lipid peroxidation, may be related to reduction of ADMA concentration via an increase in DDAH activity.

Topics: Animals; Apolipoproteins E; Arginine; Atherosclerosis; Catalase; Erythrocyte Deformability; Erythrocytes; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Superoxide Dismutase; Xanthones

Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients.. ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD).. ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids.. Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.

Topics: Aged; Albuminuria; Arginine; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (beta = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (beta = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (beta = 1.39; 95% CI, -5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level.

Topics: Adult; Arginine; Atherosclerosis; Female; Humans; Insulin Resistance; Male; Middle Aged

Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with diabetes. It has also been reported that elevated plasma levels of ADMA are associated with increased risks of nonfatal stroke and myocardial infarction in patients with early diabetic nephropathy. These findings suggest that the elevated ADMA in diabetes could contribute to acceleration of atherosclerosis in this population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs are involved in the development and progression of atherosclerosis in patients with diabetes. Since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the impairment of DDAH actions by AGEs could be one possible molecular mechanism of the ADMA elevation in diabetic patients. In this paper, we would like to propose the possible ways of testing our hypotheses. Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the levels of ADMA in diabetic patients? If the answer is yes, is this beneficial effect of metformin superior to that of other anti-diabetic agents with equihypoglycemic properties? Does treatment with pyridoxamine, a post-Amadori inhibitor (so-called Amadorins) of AGE formation, also reduce the levels of ADMA and subsequently improve endothelial dysfunction in diabetic patients? Are the ADMA-lowering effects of these agents associated with an increase of DDAH expression and/or activity in endothelial cells? These clinical studies could clarify whether AGEs are involved in the elevation of ADMA in patients with diabetes via suppression of DDAH expression and/or activity, thus providing a novel molecular mechanism for accelerated atherosclerosis in diabetes.

Topics: Arginine; Atherosclerosis; Cell Physiological Phenomena; Diabetic Angiopathies; Endothelium, Vascular; Enzyme Inhibitors; Glycation End Products, Advanced; Humans; Models, Biological; Nitric Oxide Synthase; Time Factors

Previous investigations have shown that the level of asymmetric dimethylarginine (ADMA) was increased in hypercholesterolemic animal and humans, and the decreased erythrocyte deformability has been suggested to be a factor contributing to atherogenesis. In the present study, we investigated the effect of ADMA, endogenous or exogenous, on atherogenesis and erythrocyte deformability in apolipoprotein E deficient (ApoE-/-) mice. On a regular chow diet, ApoE-/- mice or C57BL/6 J mice at 12 weeks of age were treated with ADMA (5 mg/kg/day) for 4 weeks. Atherosclerotic lesion area, erythrocyte deformability, plasma lipids and asymmetric dimethylarginine (ADMA) level were determined. Plasma concentrations of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), ADMA, and atherosclerotic lesion area were significantly increased, and the level of plasma high-density lipoprotein-cholesterol (HDL-C), erythrocyte deformability in ApoE-/- mice were markedly decreased compared with that of C57BL/6J mice (P<0.05 or P<0.01). Exogenous ADMA treatment increased the plasma TG level, produced atherosclerotic lesions, and decreased erythrocyte deformability in C57BL/6J mice (P<0.05 or P<0.01). Treatment with exogenous ADMA further increased the plasma TG level and lesion areas, and decreased erythrocyte deformability in ApoE-/- mice. In vitro, exogenous ADMA caused a decrease of erythrocyte deformability in a concentration-dependent manner, and the effect of ADMA was reversed by L-arginine. The present results suggest that endogenous ADMA is an important contributor to the development of atherosclerosis and that reduction of erythrocyte deformability and impaired endothelial function induced by ADMA may be an important factor facilitating atherosclerotic lesions.

Topics: Animals; Aorta; Apolipoproteins E; Arginine; Atherosclerosis; Disease Models, Animal; Erythrocyte Deformability; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Rats

Asymmetrical dimethylarginine (ADMA) is an inhibitor of nitric-oxide synthase. It has been linked to atherosclerotic risk in the general population as well as in end-stage renal disease patients (ESRD), whereas symmetrical dimethylarginine (SDMA) is thought to be biological inactive. Prospective data concerning the role of both dimethylarginines are rare in patients with chronic kidney disease.. 200 Patients with chronic kidney disease (mean age 57.6 +/- 13.0 years, 69 female, 131 male); 82 with chronic renal failure (CRF), 81 on maintenance haemodialysis (HD) and 37 renal transplant recipients (RTR) were prospectively followed for 24 months. ADMA and SDMA were measured by HPLC. The relation of plasma levels of ADMA and SDMA together with conventional risk factors for the cardiovascular and renal outcome was investigated with Cox proportional hazards model.. Mean serum levels of SDMA were significantly increased in all groups compared to the control group (P

Topics: Adult; Aged; Arginine; Atherosclerosis; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Proportional Hazards Models; Risk Factors