Relationship between obesity, smoking and the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA)

Center for Clinical Research, Ullevaal University Hospital, NO-0407 Oslo, Norway.
Metabolism (Impact Factor: 3.89). 12/2004; 53(12):1574-9. DOI: 10.1016/j.metabol.2004.06.026
Source: PubMed


We investigated the levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide (NO), as related to metabolic risk factors known to contribute to atherosclerotic disease. Dimethylarginines were analysed in a cross-sectional study of 563 elderly high-risk men (70 +/- 6 years). ADMA and the l-arginine/ADMA (l-arg/ADMA) ratio were highly significantly correlated with several metabolic risk factors. However, only the association with body mass index (BMI) remained significant after adjustment for inter-related variables. When analyzing the results according to being overweight or not, ADMA levels were independently significantly higher (P = .05) and the L-arg/ADMA ratios were significantly lower (P < .008) in individuals with high BMI (> or =26 kg/m(2), median value) as compared with subjects with low BMI. ADMA levels were furthermore significantly lower (P = .037) and L-arginine and the l-arg/ADMA ratios were significantly higher (P = .004 and P = .001, respectively) in smokers compared with nonsmokers, the latter being independent of other risk factors. The strong relationship found between BMI and plasma levels of ADMA and the l-arg/ADMA ratio indicate a link to endothelial dysfunction in overweight subjects. The beneficial dimethylarginine profile observed in smokers in this elderly population is not easily explainable and should be further investigated.

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    • "Although the presented experimental and genetic data suggest reciprocal and stimulatory interactions between the L-arginine-NO pathway and metabolic sensitivity to insulin [22,39,41,45,46], there are conflicting reports on the relationship between ADMA and IR in clinical conditions [13-23]. Intriguingly, we detected no correlation between ADMA and the HOMA-IR index, in accordance with the data by Mittermayer et al. [13] who described an independent relationship between higher ADMA levels 14–16 weeks after delivery with future deterioration of glucose tolerance in 18 out of 77 women with previous gestational diabetes mellitus who progressed to impaired glucose tolerance in 9 and developed new-onset type 2 diabetes in further 9 cases after a median follow-up of almost 3 years. "
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    ABSTRACT: Background Endothelial dysfunction, largely dependent on impaired nitric oxide bioavailability, has been reportedly associated with incident type 2 diabetes. Our aim was to test the hypothesis that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, might be linked to future deterioration in glucose tolerance in stable coronary artery disease (CAD). Methods We studied 80 non-diabetic men (mean age 55 ± 11 years) with stable angina who underwent successful elective complex coronary angioplasty and were receiving a standard medication according to practice guidelines. Plasma ADMA and its structural isomer symmetric dimethylarginine (SDMA) were measured prior to coronary angiography. An estimate of insulin resistance by homeostasis model assessment (HOMA-IR index) was calculated from fasting insulin and glucose. Deterioration in glucose tolerance was defined as development of type 2 diabetes or progression from a normal glucose tolerance to impaired fasting glucose. Results Over a median follow-up of 55 months 11 subjects developed type 2 diabetes and 13 progressed to impaired fasting glucose. Incident deterioration of glucose tolerance was associated with ADMA (hazard ratio [HR] per 1-SD increment 1.64 [95% CI: 1.14–2.35]; P = 0.007), log (HOMA-IR index) (HR = 1.60 [1.16–2.20]; P = 0.004) and body-mass index (HR = 1.44 [0.95–2.17]; P = 0.08) by univariate Cox regression. ADMA (HR = 1.65 [1.14–2.38]; p = 0.008) and log (HOMA-IR index) (HR = 1.55 [1.10–2.17]; P = 0.01) were multivariate predictors of a decline in glucose tolerance. ADMA and SDMA were unrelated to body-mass index, HOMA-IR index, insulin or glucose. Conclusions ADMA predicts future deterioration of glucose tolerance independently of baseline insulin resistance in men with stable CAD. Whether this association reflects a contribution of endothelial dysfunction to accelerated decline of insulin sensitivity, or represents only an epiphenomenon accompanying pre-diabetes, remains to be elucidated. The observed relationship might contribute to the well-recognized ability of ADMA to predict cardiovascular outcome.
    Full-text · Article · Apr 2013 · Cardiovascular Diabetology
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    • "Importantly, hypertension reduces bioavailability of NO and increases oxidative stress, due to increased Reactive Oxygen Species (ROS) generation and lower antioxidant capacity. In addition, Asymmetric DiMethyl Arginine (ADMA), a natural inhibitor of eNOS, has been found in higher concentrations in obese individuals [32] "
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    ABSTRACT: The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.
    Full-text · Article · Apr 2013 · Oxidative Medicine and Cellular Longevity
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    • "As cigarette smoke represents the main risk factor for COPD, several studies have investigated the relationship between cigarette smoking and ADMA levels. While some studies have found decreased ADMA levels in smokers as compared to non-smokers, others have detected increased amounts of ADMA in cigarette smoking subjects [130,131]. Despite conflicting results on arginine metabolism in COPD patients, altered ADMA levels in smokers might be associated with dysregulated PRMT activities and the ubiquitin-proteasome system, an ATP-dependent proteolytic pathway, which has been implicated in the ADMA metabolism [36,37]. "
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    ABSTRACT: Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
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