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Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs.

Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, Agrawal A - PLoS ONE (2015)

Bottom Line: Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect.Exhaled NO was reduced in both these groups.This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India.

ABSTRACT
Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.

No MeSH data available.


Related in: MedlinePlus

High-fat or high-sugar diets lead to increased ADMA associated oxo-nitrative stress and organelle dysfunction, independent of obesity.(A) ADMA levels were estimated from CN, HFA and HFR mice in total lung protein (TLP). (B) L-Arigine/ADMA ratio in lung. (C) ADMA levels in serum. (D) Nitrotyrosine levels in lung cytosolic fraction. All data are Mean ± SE. n = 6 mice in each group.*Denotes statistically significant differences (P<0.05) vs. Control.
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pone.0129850.g003: High-fat or high-sugar diets lead to increased ADMA associated oxo-nitrative stress and organelle dysfunction, independent of obesity.(A) ADMA levels were estimated from CN, HFA and HFR mice in total lung protein (TLP). (B) L-Arigine/ADMA ratio in lung. (C) ADMA levels in serum. (D) Nitrotyrosine levels in lung cytosolic fraction. All data are Mean ± SE. n = 6 mice in each group.*Denotes statistically significant differences (P<0.05) vs. Control.

Mentions: To determine whether reduced exhaled NO was related to reduced L-arginine availability and uncoupling of Nitric-Oxide-Synthase (NOS) by asymmetric dimethyl arginine (ADMA), we measured L-arginine levels in mice lungs and ADMA levels in serum and lungs of mice from all groups. The L-arginine level in pooled lungs of HFA mice (150.44 ppm by HPLC) was lower than that of CN mice (209.38 ppm) or HFR mice (199.55 ppm). ADMA was significantly increased in the lungs of HFA and HFR mice, compared to CN mice (Fig 3A). ADMA levels were also increased in serum of HFA mice compared to CN mice (Fig 3B). The lung L-arginine/ADMA ratio, reflecting local arginine bioavailability for NO production, was therefore reduced in both models of metabolic syndrome (Fig 3C). Other than reducing availability of L-arginine, ADMA has also been postulated to play a major role in asthma, where it significantly contributes to oxo-nitrative stress via generation of superoxide anions (O2−) by uncoupled NOS, which reacts with NO in the airway cells leading to the formation of peroxynitrite, a highly reactive oxidant species [40]. We thus hypothesized that increased levels of ADMA may be responsible for oxo-nitrative stress and organelle dysfunction. Since peroxynitrite is unstable, but reacts with tyrosine residues in proteins to form the stable product nitrotyrosine, we measured nitrotyrosine levels in lung homogenates by competitive ELISA method. Nitrotyrosine was increased in HFA and HFR mice, compared to CN mice (Fig 3D).


Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs.

Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, Agrawal A - PLoS ONE (2015)

High-fat or high-sugar diets lead to increased ADMA associated oxo-nitrative stress and organelle dysfunction, independent of obesity.(A) ADMA levels were estimated from CN, HFA and HFR mice in total lung protein (TLP). (B) L-Arigine/ADMA ratio in lung. (C) ADMA levels in serum. (D) Nitrotyrosine levels in lung cytosolic fraction. All data are Mean ± SE. n = 6 mice in each group.*Denotes statistically significant differences (P<0.05) vs. Control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476757&req=5

pone.0129850.g003: High-fat or high-sugar diets lead to increased ADMA associated oxo-nitrative stress and organelle dysfunction, independent of obesity.(A) ADMA levels were estimated from CN, HFA and HFR mice in total lung protein (TLP). (B) L-Arigine/ADMA ratio in lung. (C) ADMA levels in serum. (D) Nitrotyrosine levels in lung cytosolic fraction. All data are Mean ± SE. n = 6 mice in each group.*Denotes statistically significant differences (P<0.05) vs. Control.
Mentions: To determine whether reduced exhaled NO was related to reduced L-arginine availability and uncoupling of Nitric-Oxide-Synthase (NOS) by asymmetric dimethyl arginine (ADMA), we measured L-arginine levels in mice lungs and ADMA levels in serum and lungs of mice from all groups. The L-arginine level in pooled lungs of HFA mice (150.44 ppm by HPLC) was lower than that of CN mice (209.38 ppm) or HFR mice (199.55 ppm). ADMA was significantly increased in the lungs of HFA and HFR mice, compared to CN mice (Fig 3A). ADMA levels were also increased in serum of HFA mice compared to CN mice (Fig 3B). The lung L-arginine/ADMA ratio, reflecting local arginine bioavailability for NO production, was therefore reduced in both models of metabolic syndrome (Fig 3C). Other than reducing availability of L-arginine, ADMA has also been postulated to play a major role in asthma, where it significantly contributes to oxo-nitrative stress via generation of superoxide anions (O2−) by uncoupled NOS, which reacts with NO in the airway cells leading to the formation of peroxynitrite, a highly reactive oxidant species [40]. We thus hypothesized that increased levels of ADMA may be responsible for oxo-nitrative stress and organelle dysfunction. Since peroxynitrite is unstable, but reacts with tyrosine residues in proteins to form the stable product nitrotyrosine, we measured nitrotyrosine levels in lung homogenates by competitive ELISA method. Nitrotyrosine was increased in HFA and HFR mice, compared to CN mice (Fig 3D).

Bottom Line: Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect.Exhaled NO was reduced in both these groups.This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India.

ABSTRACT
Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.

No MeSH data available.


Related in: MedlinePlus