An Association between l-Arginine/Asymmetric Dimethyl Arginine Balance, Obesity, and the Age of Asthma Onset Phenotype

Abstract

Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FE NO ). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late-(r ¼ 20.4, P ¼ 0.0006) in contrast to the early-onset phenotype (r ¼ 20.2, P ¼ 0.07). Although FE NO was inversely associated with BMI in the late-onset phenotype (P ¼ 0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. Conclusions: In late-onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to FE NO . In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.Keywords: asthma; obesity; age of asthma onset; ADMA; arginine The extent to which obesity affects the health of people with asthma, and by what mechanisms, remains largely undetermined. Although adiposity imposes an important load on the respiratory system, beyond worsening dyspnea, there is little evidence that obesity affects asthma by increasing traditional biomarkers of airway inflammation or bronchial hyperresponsiveness. In fact, increasing body mass index (BMI) has been paradoxically associated with reduced levels of fractional exhaled nitric oxide (FE NO ) and sputum eosinophils (1-4). In addition, cluster analyses identify obesity as part of a phenotype characterized by less atopy and adult-onset asthma, with additional analyses suggesting obesity may be causally related to asthma among those with adult-onset asthma with less atopy (5, 6). In contrast, in those with childhood-onset more atopic asthma, the asthma appears to be causative for the weight gain (7). This difference in relationship among early-and late-onset asthma was conditionally confirmed in a study of obese subjects with asthma undergoing bariatric surgery (8). Loss of body weight improved respiratory Author Contributions: Contributed to manuscript preparation and design: F.H., S.S.K., S.C.E., S.E.W. Analyzed samples: S.C.E., R.W.P., S.L.H., S.A.A.C. Contributed with participant recruitment/sample: S.S.K., E.R.B., W.W.B., W.J.C., M.C., A.M.F., B.G., E.I., N.N.J., W.C.M., S.P.P., W.G.T., K.F.C., S.C.E., S.E.W.Correspondence and requests for reprints should be addressed to Fernando Holguin, M.D., M.P.H., Asthma Institute, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, MUH 628, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: holguinf@upmc.edu This article has an on...

Exhaled Breath Condensate Nitrate Levels are Inversely Associated with the Body Mass Index of Patients without Respiratory Disease

“…Our measured concentrations of ADMA, SDMA and arginine in EBC samples are similar to those reported in healthy adolescents [51] and adults [55]. We did not observe significant differences in BMI-classified patients on concentrations of ADMA, arginine/ADMA or nitrate/ ADMA ratios in EBC or plasma samples, but these may be specific findings to obesity-related asthma [22].…”

“…Endothelial NOS dysfunction decreases NO-dependent vasodilation and contributes to hypertension and other cardiovascular complications often seen with obesity [20]. Recent studies focused on obesity-related asthma in adults suggest that obese adult asthmatics have a reduced fractional NO concentration in exhaled air (FeNO) related to an impairment in the arginine/ADMA pathway [22,23]. Moreover, FeNO increases in morbidly obese patients without asthma after weight loss following bariatric surgery [24].…”

Relationship between cysteinyl leukotrienes and nitric oxide in the pathogenesis of asthma in obesity

“…It was also decreased in obese asthmatics compared to non-obese asthmatics. Reduced arginine / asymmetric dimethyl arginine ratio in obesity may explain this phenomenon [26]. The negative correlation between FeNO and the female gender (who made up ~65% of subjects) compared to males may also be influencing this finding.…”

“…Others have shown that there is a negative correlation between BMI and FeNO in asthma [25]. Investigators have demonstrated increased asymmetric di-methyl arginine compared to Larginine in obesity [26]. This uncouples NO synthase leading to lowered FeNO.…”

Update in Asthma 2013

“…To define pathways to explain differences in inflammatory patterns in obese patients with asthma, Holguin and colleagues measured the formation of asymmetric dimethyl arginine (ADMA), a product of posttranslational methylation of L-arginine and an L-arginine analog that inhibits both the inducible and constitutive forms of nitric oxide synthases (18). ADMA formation results in uncoupling of nitric oxide synthase, reduced NO synthesis, and increased oxidant production, and ADMA is increased in obesity (19).…”