Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections

Zoccali, Carmine; Maas, Renke; Cutrupi, Sebastiano; Pizzini, Patrizia; Finocchiaro, Piero; Cambareri, Francesco; Panuccio, Vincenzo; Martorano, C.; Schulze, Friedrich; Enia, Giuseppe; Tripepi, Giovanni; Böger, Rainer H.

doi:10.1093/ndt/gfl719

Cited by 76 publications

(63 citation statements)

References 29 publications

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“…A partly discrepant finding was reported by Zoccali et al, who found normal ADMA in patients with acute inflammation and underlying chronic disease with a variable degree of renal insufficiency and a rise in ADMA once the source of inflammation was treated; no such association was found for SDMA (36). Our data, however, refer to the chronic moderate inflammation in CKD in contrast to the study by Zoccali et al, which refers to acute bacterial infection episodes.…”

Section: Discussioncontrasting

confidence: 99%

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Schepers¹,

Barreto²,

Liabeuf³

et al. 2011

Clinical Journal of the American Society of Nephrology

129

107

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SummaryBackground & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurementsIn vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-␣ was studied followed by an evaluation of nuclear factor (NF)-B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.Results Monocytes incubated with SDMA showed increased IL-6 and TNF-␣ expression and a rise in active NF-B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 Ϯ 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-␣, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-␣ at a high significance for SDMA (P Ͻ 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 Ϯ 0.05) directly followed that of C-reactive protein (AUC: 0.82 Ϯ 0.04) and albumin (AUC: 0.72 Ϯ 0.05; for all, P Ͻ 0.0001) and preceded that of ADMA (P ϭ 0.002). ConclusionsThe present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-B and resulting in enhanced expression of IL-6 and TNF-␣, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.

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Section: Discussioncontrasting

confidence: 99%

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Schepers¹,

Barreto²,

Liabeuf³

et al. 2011

Clinical Journal of the American Society of Nephrology

129

107

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“…A decline in ADMA as a response to inflammation in acute infections was documented by Zoccali et al (31), an observation with which our findings are in line.…”

Section: Adma Levels Influenced By Enhanced Inflammation Affects Glsupporting

confidence: 93%

“…ADMA values were dichotomized by the median value (0.68 μmol/L). Due to skewed distribution, values derived from log-transformed Onat et al Apparently "low" asymmetric dimethylarginine Anadolu Kardiyol Derg 2014; 14: [26][27][28][29][30][31][32][33] (geometric) means were used for ADMA and six other variables. For such variables, an SD value of (for example) 1.7 indicates the factor needed to multiply or divide the mean value to obtain the limits of the SD.…”

Section: Discussionmentioning

confidence: 99%

Apparently “low” serum asymmetric dimethylarginine is associated with fasting glucose and tends toward association with type-2 diabetes

Onat¹,

Köroğlu²,

Can³

et al. 2013

Anadolu Kardiyol Derg

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Objective: We investigated the association of serum asymmetric dimethylarginine (ADMA) with metabolic syndrome (MetS), type-2 diabetes and coronary heart disease (CHD) in the general population. Methods: Cross-sectional and, at 2000 person-years' follow-up, prospective analysis. Adults with measured serum ADMA level (n=848) were analyzed using tertiles or dichotomized values. ADMA concentrations were measured by a validated commercial ELISA kit. Results: Dichotomized subjects of combined sexes with low (≤0.68 μmol/L) ADMA values had significantly higher fasting glucose, total cholesterol, apolipoprotein B and lower diastolic blood pressure. In linear regression analyses comprising age, smoking, triglyceride, HDL-cholesterol, C-reactive protein and waist circumference as well, creatinine was significantly and independently associated with ADMA, further in women glucose (inversely). In logistic regression analyses uniformly adjusted for age, smoking status and waist girth, prevalent MetS tended to positive independent association with ADMA tertiles only in men. Combined prevalent and incident diabetes weakly tended to be associated with the lowest (vs mid-and highest) ADMA tertiles in combined gender; and prevalent and incident CHD was not associated with ADMA tertiles in either sex. Conclusion: Apparently "low" circulating ADMA is independently associated with fasting glucose and tends to be so with type-2 diabetes. The lack of anticipated positive associations of ADMA with cardiometabolic disorders is likely due to autoimmune responses operating against serum ADMA under oxidative stress, rendering partial failure in immunoassay. (Anadolu Kardiyol Derg 2014; 14: 26-33)

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“…18 However, in acute infections (a model of lipopolysaccharide-mediated inflammation in humans), ADMA was increased by the end of infection period, 22 suggesting that the type of underlying inflammatory stimuli plays a crucial role in ADMA regulation. Therefore, the causal association among low-grade inflammation, ADMA, and endothelial dysfunction needs to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

et al. 2011

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Abstract-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 (nϭ11 healthy and nϭ60 CAD) or placebo (nϭ11 healthy and nϭ10 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 (PϽ0.0001 for both). However, interleukin 6 was inversely correlated with FMD (PϽ0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (rϭ0.515; PϽ0.0001) compared with CAD (rϭ0.289; Pϭ0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (PϽ0.0001) and ADMA (Pϭ0.004) but lower FMD (Pϭ0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (PϽ0.001) and CAD (PϽ0.001) subjects. FMD was reduced in healthy subjects (PϽ0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (PϽ0.001). 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. (Hypertension. 2011;58:93-98.) • Online Data Supplement Key Words: ADMA Ⅲ endothelium Ⅲ inflammation Ⅲ interleukin 6 Ⅲ atherosclerosis Ⅲ coronary artery disease T he development of endothelial dysfunction is considered to be the initial step in atherogenesis. 1 A healthy endothelium is responsible for NO generation through oxidation of L-arginine by endothelial NO synthase (eNOS). 1 NO maintains vascular tone and acts, per se, as an important intracellular messenger, inducing divergent anti-inflammatory, antithrombotic, and antiapoptotic effects. 1 Asymmetrical dimethylarginine (ADMA), an endogenous L-arginine analog, has been associated with impaired endothelial function in humans. 2 ADMA has also been associated with eNOS uncoupling that results in increased eNOSderived superoxide production in human vessels. 2 Clinical evidence suggests that ADMA plasma levels are associated with endothelial function, particularly in patients with coronary atherosclerosis 3 or atherosclerosis risk factors, 4 whereas this association is significant but weak in healthy individuals. 5 Furthermore, in prospective studies, plasma ADMA has been independently associated with clinical outcome and mortality in diabetic subjects and patients with atherosclerosis. 6 ADMA is derived from ...

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Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections

Cited by 76 publications

References 29 publications

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Apparently “low” serum asymmetric dimethylarginine is associated with fasting glucose and tends toward association with type-2 diabetes

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

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